bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2021–12–05
sixty-one papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Metabolic reprogramming by driver mutation-tumor microenvironment interplay in pancreatic cancer: new therapeutic targets.
  2. Targeting cancer metabolism in the era of precision oncology.
  3. Targeting the metabolism of cancer stem cells by energy disruptor molecules.
  4. Cancer metabolism and tumor microenvironment: fostering each other?
  5. What do cellular responses to acidity tell us about cancer?
  6. Too complex to fail? Targeting fatty acid metabolism for cancer therapy.
  7. Pharmacological Targeting of Ferroptosis in Cancer Treatment.
  8. Novel perspective in pancreatic cancer therapy: Targeting ferroptosis pathway.
  9. The Dichotomous Effect of Thiamine Supplementation on Tumorigenesis: A Systematic Review.
  10. Immunotherapy for cancer: effects of iron oxide nanoparticles on polarization of tumor-associated macrophages.
  11. p53: A Double-Edged Sword in Tumor Ferroptosis.
  12. Autophagy: A Promising Target for Triple Negative Breast Cancers.
  13. Cellular defense system-destroying nanoparticles as a platform for enhanced chemotherapy against drug-resistant cancer.
  14. Glutamine deprivation triggers NAGK-dependent hexosamine salvage.
  15. Nanotherapeutics for immune network modulation in tumor microenvironments.
  16. Targeting Production of Reactive Oxygen Species as an Anticancer Strategy.
  17. Targeting the Tumor Microenvironment: A Literature Review of the Novel Anti-Tumor Mechanism of Statins.
  18. Vitamin D endocrine system in breast cancer.
  19. Recent advances in targeted nanotherapeutic approaches for breast cancer management.
  20. Molecular Mechanisms of Cancer Prevention by Gooseberry (Phyllanthus emblica).
  21. Role of Flavonoids as Epigenetic Modulators in Cancer Prevention and Therapy.
  22. Platycodin D inhibits the malignant progression of papillary thyroid carcinoma by NF-κB and enhances the therapeutic efficacy of pembrolizumab.
  23. Evaluation of Erastin as a Therapeutic Agent Under Hypoxic Conditions in Pancreatic Cancer Cells.
  24. Redrawing therapeutic boundaries: microbiota and cancer.
  25. Precise Chemodynamic Therapy of Cancer by Trifunctional Bacterium-Based Nanozymes.
  26. Repurposing hyperpolarization-activated cyclic nucleotide-gated channels as a novel therapy for breast cancer.
  27. Hydroxychloroquine synergizes with the PI3K inhibitor BKM120 to exhibit antitumor efficacy independent of autophagy.
  28. PSMA-targeted arsenic nanosheets: a platform for prostate cancer therapy via ferroptosis and ATM deficiency-triggered chemosensitization.
  29. Identifying the Effect of Ursolic Acid Against Triple-Negative Breast Cancer: Coupling Network Pharmacology With Experiments Verification.
  30. Periodic mesoporous organosilica coupled with chlorin e6 and catalase for enhanced photodynamic therapy to treat triple-negative breast cancer.
  31. Multifunctional FeS2@SRF@BSA nanoplatform for chemo-combined photothermal enhanced photodynamic/chemodynamic combination therapy.
  32. Plasmon-Triggered Upconversion Emissions and Hot Carrier Injection for Combinatorial Photothermal and Photodynamic Cancer Therapy.
  33. Factor VIII as a potential player in cancer pathophysiology.
  34. Quantifying and controlling bond multivalency for advanced nanoparticle targeting to cells.
  35. Metal-Phenolic Network-Coated Dendrimer-Drug Conjugates for Tumor MR Imaging and Chemo/Chemodynamic Therapy via Amplification of Endoplasmic Reticulum Stress.
  36. An Update on Vitamin D Deficiency in the twenty-first century: nature and nurture.
  37. Biocompatible Mesoporous Silica-Polydopamine Nanocomplexes as MR/Fluorescence Imaging Agent for Light-Activated Photothermal-Photodynamic Cancer Therapy In Vivo.
  38. Oligonucleotides carrying nucleoside antimetabolites as potential prodrugs.
  39. Rare and potentially pathogenic variants in hydroxycarboxylic acid receptor genes identified in breast cancer cases.
  40. A Metabolomic Investigation of Eugenol on Colorectal Cancer Cell Line HT-29 by Modifying the Expression of APC, p53, and KRAS Genes.
  41. Prussian Blue/Calcium Peroxide Nanocomposites-Mediated Tumor Cell Iron Mineralization for Treatment of Experimental Lung Adenocarcinoma.
  42. Amphiphilic Fullerene-BODIPY Photosensitizers for Targeted Photodynamic Therapy.
  43. Circulating low density neutrophils of breast cancer patients are associated with their worse prognosis due to the impairment of T cell responses.
  44. Construction of tellurium-doped mesoporous bioactive glass nanoparticles for bone cancer therapy by promoting ROS-mediated apoptosis and antibacterial activity.
  45. Impact of carbamazepine on vitamin D levels: A meta-analysis.
  46. Systematic characterization of the metabolites of defatted walnut powder extract in vivo and screening of the mechanisms against NAFLD by UPLC-Q-Exactive Orbitrap MS combined with network pharmacology.
  47. To explore immune synergistic function of Quercetin in inhibiting breast cancer cells.
  48. Cysteine and iron accelerate the formation of ribose-5-phosphate, providing insights into the evolutionary origins of the metabolic network structure.
  49. Two-step fabricating micelle-like nanoparticles of cisplatin with the 'real' long circulation and high bioavailability for cancer therapy.
  50. Chlorogenic acid: Potential source of natural drugs for the therapeutics of fibrosis and cancer.
  51. Emerging trends in the application of gold nanoformulations in colon cancer diagnosis and treatment.
  52. Traditional Chinese Medicine for adjuvant treatment of breast cancer: Taohong Siwu Decoction.
  53. Tumor Cell Distinguishable Nanomedicine Integrating Chemotherapeutic Sensitization and Protection.
  54. Clinical Trials in Spinal Tumors: A Two-Decade Review.
  55. Breast cancer vaccines for treatment and prevention.
  56. High-frequency irreversible electroporation brain tumor ablation: exploring the dynamics of cell death and recovery.
  57. Nanocarriers targeting the diseases of the pancreas.
  58. Pharmacological potentials and Nutritional values of Tropical and Sub-tropical Fruits of India: Emphasis on their anticancer bioactive components.
  59. Old wine in new bottles: kaempferol is a promising agent for treating the trilogy of liver diseases.
  60. New Challenges in the Use of Nanomedicine in Cancer Therapy.
  61. Pan-cancer analysis of non-oncogene addiction to DNA repair.
  1. Cancer Metastasis Rev. 2021 Dec 02.
    Metabolic reprogramming by driver mutation-tumor microenvironment interplay in pancreatic cancer: new therapeutic targets.
    Henriette Berg Andersen, Renata Ialchina, Stine Falsig Pedersen, Dominika Czaplinska.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers globally with a mortality rate exceeding 95% and very limited therapeutic options. A hallmark of PDAC is its acidic tumor microenvironment, further characterized by excessive fibrosis and depletion of oxygen and nutrients due to poor vascularity. The combination of PDAC driver mutations and adaptation to this hostile environment drives extensive metabolic reprogramming of the cancer cells toward non-canonical metabolic pathways and increases reliance on scavenging mechanisms such as autophagy and macropinocytosis. In addition, the cancer cells benefit from metabolic crosstalk with nonmalignant cells within the tumor microenvironment, including pancreatic stellate cells, fibroblasts, and endothelial and immune cells. Increasing evidence shows that this metabolic rewiring is closely related to chemo- and radioresistance and immunosuppression, causing extensive treatment failure. Indeed, stratification of human PDAC tumors into subtypes based on their metabolic profiles was shown to predict disease outcome. Accordingly, an increasing number of clinical trials target pro-tumorigenic metabolic pathways, either as stand-alone treatment or in conjunction with chemotherapy. In this review, we highlight key findings and potential future directions of pancreatic cancer metabolism research, specifically focusing on novel therapeutic opportunities.
    Keywords:  Acidosis; Clinical trials; Glycolysis; Lipid metabolism; Metabolic subtypes; PDAC
    DOI:  https://doi.org/10.1007/s10555-021-10004-4
  2. Nat Rev Drug Discov. 2021 Dec 03.
    Targeting cancer metabolism in the era of precision oncology.
    Zachary E Stine, Zachary T Schug, Joseph M Salvino, Chi V Dang.
      One hundred years have passed since Warburg discovered alterations in cancer metabolism, more than 70 years since Sidney Farber introduced anti-folates that transformed the treatment of childhood leukaemia, and 20 years since metabolism was linked to oncogenes. However, progress in targeting cancer metabolism therapeutically in the past decade has been limited. Only a few metabolism-based drugs for cancer have been successfully developed, some of which are in - or en route to - clinical trials. Strategies for targeting the intrinsic metabolism of cancer cells often did not account for the metabolism of non-cancer stromal and immune cells, which have pivotal roles in tumour progression and maintenance. By considering immune cell metabolism and the clinical manifestations of inborn errors of metabolism, it may be possible to isolate undesirable off-tumour, on-target effects of metabolic drugs during their development. Hence, the conceptual framework for drug design must consider the metabolic vulnerabilities of non-cancer cells in the tumour immune microenvironment, as well as those of cancer cells. In this Review, we cover the recent developments, notable milestones and setbacks in targeting cancer metabolism, and discuss the way forward for the field.
    DOI:  https://doi.org/10.1038/s41573-021-00339-6
  3. Crit Rev Oncol Hematol. 2021 Nov 24. pii: S1040-8428(21)00332-2. [Epub ahead of print]169 103545
    Targeting the metabolism of cancer stem cells by energy disruptor molecules.
    Tahere Dadgar, Nasim Ebrahimi, Amir Reza Gholipour, Maryam Akbari, Leila Khani, Amirhossein Ahmadi, Michael R Hamblin.
      Cancer stem cells (CSCs) have been identified in various tumor types. CSCs are believed to contribute to tumor metastasis and resistance to conventional therapy. So targeting these cells could be an effective strategy to eliminate tumors and a promising new type of cancer treatment. Alterations in metabolism play an essential role in CSC biology and their resistance to treatment. The metabolic properties pathways in CSCs are different from normal cells, and to some extent, are different from regular tumor cells. Interestingly, CSCs can use other nutrients for their metabolism and growth. The different metabolism causes increased sensitivity of CSCs to agents that disrupt cellular homeostasis. Compounds that interfere with the central metabolic pathways are known as energy disruptors and can reduce CSC survival. This review highlights the differences between regular cancer cells and CSC metabolism and discusses the action mechanisms of energy disruptors at the cellular and molecular levels.
    Keywords:  Cancer; Cancer stem cells; Energy disruptors; Metabolism
    DOI:  https://doi.org/10.1016/j.critrevonc.2021.103545
  4. Sci China Life Sci. 2021 Nov 26.
    Cancer metabolism and tumor microenvironment: fostering each other?
    Yiyuan Yuan, Huimin Li, Wang Pu, Leilei Chen, Dong Guo, Hongfei Jiang, Bo He, Siyuan Qin, Kui Wang, Na Li, Jingwei Feng, Jing Wen, Shipeng Cheng, Yaguang Zhang, Weiwei Yang, Dan Ye, Zhimin Lu, Canhua Huang, Jun Mei, Hua-Feng Zhang, Ping Gao, Peng Jiang, Shicheng Su, Bing Sun, Shi-Min Zhao.
      The changes associated with malignancy are not only in cancer cells but also in environment in which cancer cells live. Metabolic reprogramming supports tumor cell high demand of biogenesis for their rapid proliferation, and helps tumor cell to survive under certain genetic or environmental stresses. Emerging evidence suggests that metabolic alteration is ultimately and tightly associated with genetic changes, in particular the dysregulation of key oncogenic and tumor suppressive signaling pathways. Cancer cells activate HIF signaling even in the presence of oxygen and in the absence of growth factor stimulation. This cancer metabolic phenotype, described firstly by German physiologist Otto Warburg, insures enhanced glycolytic metabolism for the biosynthesis of macromolecules. The conception of metabolite signaling, i.e., metabolites are regulators of cell signaling, provides novel insights into how reactive oxygen species (ROS) and other metabolites deregulation may regulate redox homeostasis, epigenetics, and proliferation of cancer cells. Moreover, the unveiling of noncanonical functions of metabolic enzymes, such as the moonlighting functions of phosphoglycerate kinase 1 (PGK1), reassures the importance of metabolism in cancer development. The metabolic, microRNAs, and ncRNAs alterations in cancer cells can be sorted and delivered either to intercellular matrix or to cancer adjacent cells to shape cancer microenvironment via media such as exosome. Among them, cancer microenvironmental cells are immune cells which exert profound effects on cancer cells. Understanding of all these processes is a prerequisite for the development of a more effective strategy to contain cancers.
    Keywords:  cancer immunology; cancer metabolism; cancer microenvironment; epigenetics
    DOI:  https://doi.org/10.1007/s11427-021-1999-2
  5. Cancer Metastasis Rev. 2021 Nov 30.
    What do cellular responses to acidity tell us about cancer?
    Wiktoria Blaszczak, Pawel Swietach.
      The notion that invasive cancer is a product of somatic evolution is a well-established theory that can be modelled mathematically and demonstrated empirically from therapeutic responses. Somatic evolution is by no means deterministic, and ample opportunities exist to steer its trajectory towards cancer cell extinction. One such strategy is to alter the chemical microenvironment shared between host and cancer cells in a way that no longer favours the latter. Ever since the first description of the Warburg effect, acidosis has been recognised as a key chemical signature of the tumour microenvironment. Recent findings have suggested that responses to acidosis, arising through a process of selection and adaptation, give cancer cells a competitive advantage over the host. A surge of research efforts has attempted to understand the basis of this advantage and seek ways of exploiting it therapeutically. Here, we review key findings and place these in the context of a mathematical framework. Looking ahead, we highlight areas relating to cellular adaptation, selection, and heterogeneity that merit more research efforts in order to close in on the goal of exploiting tumour acidity in future therapies.
    Keywords:  Acid–base; Adaptation; Cell lines; Evolution; Metabolism; Phenotype; Selection; Variation; pH
    DOI:  https://doi.org/10.1007/s10555-021-10005-3
  6. Prog Lipid Res. 2021 Nov 29. pii: S0163-7827(21)00059-X. [Epub ahead of print] 101143
    Too complex to fail? Targeting fatty acid metabolism for cancer therapy.
    Rimsha Munir, Jan Lisec, Johannes V Swinnen, Nousheen Zaidi.
      Given the central role of fatty acids in cancer pathophysiology, the exploitation of fatty acid metabolism as a potential antineoplastic therapy has gained much attention. Several natural and synthetic compounds targeting fatty acid metabolism were hitherto identified, and their effectiveness against cancer cell proliferation and survival was determined. This review will discuss the most clinically viable inhibitors or drugs targeting various proteins or enzymes mapped on nine interconnected fatty acid metabolism-related processes. We will discuss the general significance of each of these processes and the effects of their inhibition on cancer cell progression. Moreover, their mechanisms of action, limitations, and future perspectives will be assessed.
    Keywords:  Cancer therapy; Fatty acid desaturation; Fatty acid synthesis; Fatty acid uptake; Fatty acids
    DOI:  https://doi.org/10.1016/j.plipres.2021.101143
  7. Curr Cancer Drug Targets. 2021 Dec 01.
    Pharmacological Targeting of Ferroptosis in Cancer Treatment.
    Mehdi Rabiee Valashedi, Amirsadegh Nikoo, Nima Najafi-Ghalehlou, Kazuo Tomita, Yoshikazu Kuwahara, Tomoaki Sato, Amaneh Mohammadi Roushandeh, Mehryar Habibi Roudkenar.
      Ferroptosis is a non-apoptotic mode of Regulated Cell Death (RCD) driven by excessive accumulation of toxic lipid peroxides and iron overload. Ferroptosis could be triggered by inhibiting the antioxidant defense system and accumulating iron-dependent Reactive Oxygen Species (ROS) that react with polyunsaturated fatty acids in abundance. Emerging evidence over the past few years has revealed that ferroptosis is of great potential in inhibiting growth and metastasis and overcoming tumor cell resistance. Thus, targeting this form of cell death could be perceived as a potentially burgeoning approach in cancer treatment. This review briefly presents the underlying mechanisms of ferroptosis and further aims to discuss various types of existing drugs and natural compounds that could be potentially repurposed for targeting ferroptosis in tumor cells. This, in turn, will provide critical perspectives on future studies concerning ferroptosis-based cancer therapy.
    Keywords:  Ferroptosis; antioxidant; cancer therapy; cell death; iron; pharmacotherapy; reactive oxygen species
    DOI:  https://doi.org/10.2174/1568009621666211202091523
  8. World J Gastrointest Oncol. 2021 Nov 15. 13(11): 1668-1679
    Novel perspective in pancreatic cancer therapy: Targeting ferroptosis pathway.
    Yang Yang, Zi-Jian Zhang, Yu Wen, Li Xiong, Yun-Peng Huang, Yong-Xiang Wang, Kai Liu.
      Pancreatic cancer is a highly lethal malignancy with low resection and survival rates and is not sensitive to radiotherapy and chemotherapy. Ferroptosis is a novel form of nonapoptotic regulated cell death characterized by the accumulation of lipid peroxides and reactive oxygen species involved in iron metabolism. Ferroptosis has a significant role in the occurrence and development of various tumors. Previous studies have shown that regulating ferroptosis-induced cell death inhibited tumor growth in pancreatic cancer and was synergistic with other antitumor drugs to improve treatment sensitivity. Herein, we discuss the mechanism, inducers, and developments of ferroptosis in pancreatic cancer to provide new strategies for the treatment of the malignancy.
    Keywords:  Ferroptosis; Iron metabolism; Lipid peroxides; Pancreatic cancer; Reactive oxygen species
    DOI:  https://doi.org/10.4251/wjgo.v13.i11.1668
  9. Nutr Cancer. 2021 Dec 02. 1-16
    The Dichotomous Effect of Thiamine Supplementation on Tumorigenesis: A Systematic Review.
    José Reginaldo Alves de Queiroz Júnior, Jarson Pedro da Costa Pereira, Leonardo Lucas Pires, Carina Scanoni Maia.
      The malignant neoplastic cell is characterized by its diverse metabolic changes. It occurs in order to maintain the high rate of proliferation. The possibility of new pharmacological targets has inserted tumor metabolism as a target for recent research, emphasizing the enzymatic activity of thiamin. This review aims to elucidate the behavior of thiamin against tumor development. This is a systematic review in which studies indexed in Pubmed, Scopus, SciELO and BVS were searched using the descriptors (Thiamin OR Vitamin B1) AND (Cancer OR Malignant neoplasia) AND (Tumor metabolism). Title and abstract were read. Duplicates, literary reviews, books, conference abstracts, editorials, and papers published prior to 2010 were eliminated. 23 records were included in this review. Low doses of thiamin have been shown to be enough to stimulate tumor growth. Another population studies has shown evidence of tumor regression after correction of vitamin B1 deficiency. There is an open path for the development of new research to better assess the influence of thiamin on cancer cells. Once the connections between thiamin and the metabolism of cancer cells are fully established, new opportunities for therapeutic intervention and dietary modification will appear to reduce the progression of the disease in patients with cancer.
    DOI:  https://doi.org/10.1080/01635581.2021.2007962
  10. Nanomedicine (Lond). 2021 Dec 02.
    Immunotherapy for cancer: effects of iron oxide nanoparticles on polarization of tumor-associated macrophages.
    Camila Sales Nascimento, Érica Alessandra Rocha Alves, Celso Pinto de Melo, Rodrigo Corrêa-Oliveira, Carlos Eduardo Calzavara-Silva.
      Cancer immunotherapy is the most promising trend in oncology, focusing on helping or activating the patient's immune system to identify and fight against cancer. In the last decade, interest in metabolic reprogramming of tumor-associated macrophages from M2-like phenotype (promoting tumor progression) to M1-like phenotypes (suppressing tumor growth) as a therapeutic strategy against cancer has increased considerably. Iron metabolism has been standing out as a target for the reprogramming of tumor-associated macrophages to M1-like phenotype with therapeutic purposes against cancer. Due to the importance of the iron levels in macrophage polarization states, iron oxide nanoparticles can be used to change the activation state of tumor-associated macrophages for a tumor suppressor phenotype and as an anti-tumor strategy.
    Keywords:  cancer; immunometabolism; immunotherapy; iron oxide nanoparticles; metabolic reprogramming of tumor-associated macrophages
    DOI:  https://doi.org/10.2217/nnm-2021-0255
  11. Pharmacol Res. 2021 Nov 29. pii: S1043-6618(21)00597-1. [Epub ahead of print] 106013
    p53: A Double-Edged Sword in Tumor Ferroptosis.
    Haixia Ji, Wenzhe Wang, Xia Li, Xiaoying Han, Xinyu Zhang, Juan Wang, Changxiao Liu, Luqi Huang, Wenyuan Gao.
      Ferroptosis is a type of lipid peroxidation-induced cell death that can be regulated in various ways, from changing the activity of antioxidant enzymes to the levels of transcription factors. The p53 tumor suppressor gene is the "guardian of the genome" and is involved in controlling cell survival and division under various pressures. In addition to its effects on apoptosis, autophagy, and cell cycle, p53, through the way of transcription dependent or independent two-way, also regulates the biological processes of tumor cell sensitivity to ferroptosis, including the metabolism of amino acids, nicotinamide adenine dinucleotide phosphate, and lipid peroxidation, as well as the biosynthesis of glutathione, phospholipids, NADPH and coenzyme Q10.As reviewed here, we summarized the metabolic network of p53 and its signaling pathway in regulating ferroptosis and elucidated possible factors and potential clinical application of p53 regulating ferroptosis. This review will provide a basis for further understanding the role of p53 in tumor ferroptosis and new strategies for cancer therapeutic avenues.
    Keywords:  Ferroptosis; Metabolism; P53; Sensitivity; Tumor suppressor
    DOI:  https://doi.org/10.1016/j.phrs.2021.106013
  12. Pharmacol Res. 2021 Nov 26. pii: S1043-6618(21)00590-9. [Epub ahead of print] 106006
    Autophagy: A Promising Target for Triple Negative Breast Cancers.
    Yomna S Abd El-Aziz, Josef Gillson, Patric J Jansson, Sumit Sahni.
      Triple negative breast cancer (TNBC) is the most aggressive type of breast cancers which constitutes about 15% of all breast cancer cases and characterized by negative expression of hormonal receptors and human epidermal growth factor receptor 2 (HER2). Thus, endocrine and HER2 targeted therapies are not effective toward TNBCs, and they mainly rely on chemotherapy and surgery for treatment. Despite recent advances in chemotherapy, 40% of TNBC patients develop a metastatic relapse and recurrence. Therefore, understanding the molecular profile of TNBC is warranted to identify targets that can be selected for the development of a new and effective therapeutic approach. Autophagy is an internal defensive mechanism that allows the cells to survive under different stressors. It has been well known that autophagy exerts a crucial role in cancer progression. The critical role of autophagy in TNBC progression is emerging in recent years. This review will discuss autophagic pathway, how autophagy affects TNBC progression and recent therapeutic approaches that can target autophagy as a new treatment modality.
    Keywords:  Autophagy; Autophagy Inhibitors; Triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.phrs.2021.106006
  13. Mater Sci Eng C Mater Biol Appl. 2021 Dec;pii: S0928-4931(21)00634-2. [Epub ahead of print]131 112494
    Cellular defense system-destroying nanoparticles as a platform for enhanced chemotherapy against drug-resistant cancer.
    Boyi Niu, Kaixin Liao, Yixian Zhou, Ting Wen, Guilan Quan, Chuanbin Wu, Xin Pan.
      Cellular defense system represented by glutathione (GSH) greatly weakens the outcomes of cancer therapy by antioxidation and detoxification. GSH depletion has been proved to be an effective way to enhance the efficacy of reactive oxygen species (ROS)-based therapies and chemotherapy. However, the existing strategies of GSH depletion still face the problems of unclear biosafety and high complexity of multicomponent co-delivery. In this study, we developed a GSH-depleting carrier platform based on disulfide-bridged mesoporous organosilica nanoparticles (MONs) to destroy the cellular defense system for cancer therapy. Responding to the high level of GSH in cancer cells, the disulfide bonds in the framework of MONs could be broken and consumed substantial GSH at the same time. Moreover, this process also promoted the degradation of MONs. In order to evaluate the effect of this platform in cancer therapy, chemotherapeutic drug cisplatin was loaded into MONs (Pt@MONs) to treat drug-resistant non-small cell lung cancer. In vitro and in vivo results indicated that Pt@MONs efficiently triggered GSH depletion, promoted platinum-DNA adduct formation, and induced cell apoptosis, resulting in significant tumor growth inhibition without marked toxicity. Taken together, the cellular defense system-destroying nanoparticles provide a promising platform for enhanced cancer therapy.
    Keywords:  Chemotherapy; Cisplatin resistance; Disulfide bonds; Glutathione depletion; Mesoporous organosilica nanoparticles (MONs)
    DOI:  https://doi.org/10.1016/j.msec.2021.112494
  14. Elife. 2021 11 30. pii: e62644. [Epub ahead of print]10
    Glutamine deprivation triggers NAGK-dependent hexosamine salvage.
    Sydney Campbell, Clementina Mesaros, Luke Izzo, Hayley Affronti, Michael Noji, Bethany E Schaffer, Tiffany Tsang, Kathryn Sun, Sophie Trefely, Salisa Kruijning, John Blenis, Ian A Blair, Kathryn E Wellen.
      Tumors frequently exhibit aberrant glycosylation, which can impact cancer progression and therapeutic responses. The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a major substrate for glycosylation in the cell. Prior studies have identified the HBP as a promising therapeutic target in pancreatic ductal adenocarcinoma (PDA). The HBP requires both glucose and glutamine for its initiation. The PDA tumor microenvironment is nutrient poor, however, prompting us to investigate how nutrient limitation impacts hexosamine synthesis. Here, we identify that glutamine limitation in PDA cells suppresses de novo hexosamine synthesis but results in increased free GlcNAc abundance. GlcNAc salvage via N-acetylglucosamine kinase (NAGK) is engaged to feed UDP-GlcNAc pools. NAGK expression is elevated in human PDA, and NAGK deletion from PDA cells impairs tumor growth in mice. Together, these data identify an important role for NAGK-dependent hexosamine salvage in supporting PDA tumor growth.
    Keywords:  N-acetylglucosamine kinase; cancer biology; glutamine; hexosamine; human; mouse; pancreatic cancer
    DOI:  https://doi.org/10.7554/eLife.62644
  15. Semin Cancer Biol. 2021 Nov 26. pii: S1044-579X(21)00278-9. [Epub ahead of print]
    Nanotherapeutics for immune network modulation in tumor microenvironments.
    Jaiwoo Lee, Dongyoon Kim, Quoc-Viet Le, Yu-Kyoung Oh.
      Immunotherapy has shown promise in cancer treatment, and is thus drawing increasing interest in this field. While the standard chemotherapy- and/or radiotherapy-based cancer treatments aim to directly kill cancer cells, immunotherapy uses host immune cell surveillance to fight cancer. In the tumor environment, there is a close relationship between tumor cells and the adjacent immune cells, which are largely suppressed by cancer-related regulation of immune checkpoints, immune-suppressive cytokines, and metabolic factors. The immune modulators currently approved for cancer treatment remain limited by issues with dose tolerance and insufficient efficacy. Researchers have developed and tested various nano-delivery systems with the goal of improving the treatment outcome of these drugs. By encapsulating immune modulators in particles and directing their tissue accumulation, some such systems have decreased immune-related toxicity while sharpening the antitumor response. Surface-ligand modification of nanoparticles has allowed drugs to be delivered to specific immune cells types. Researchers have also studied strategies for depleting or reprogramming the immune-suppressive cells to recover the immune environment. Combining a nanomaterial with an external stimulus has been used to induce immunogenic cell death; this favors the inflammatory environment found in tumor tissues to promote antitumor immunity. The present review covers the most recent strategies aimed at modulating the tumor immune environment, and discusses the challenges and future perspectives in developing nanoparticles for cancer immunotherapy.
    Keywords:  Cancer immunotherapy; Cytokine; Immune checkpoint inhibitor; Immune modulator; Immunogenic cell death; Metabolic; Nanoparticle
    DOI:  https://doi.org/10.1016/j.semcancer.2021.11.005
  16. Anticancer Res. 2021 Dec;41(12): 5881-5902
    Targeting Production of Reactive Oxygen Species as an Anticancer Strategy.
    Grigoria-Kalliopi Marioli-Sapsakou, Malamati Kourti.
      Cancer remains the second leading cause of death worldwide. Research is currently focused on finding novel anticancer therapies and elucidating their mechanisms of action. Cellular redox balance is a promising target for new therapies, as cancer cells already have elevated levels of oxidizing agents due to hypermetabolism and genetic instability. Although free radicals are actively involved in vital cellular signaling pathways, they have also been implicated in certain diseases, including cancer. The aim of this review was to highlight the involvement of oxidative stress in the mechanism of action of anticancer agents. The difference in cellular redox balance between normal and cancer cells is discussed as a potential anticancer target, along with various examples of approved or experimental drugs that may alter the redox state. These drugs are presented in relation to their pro-oxidant or antioxidant mechanisms, with the consequent goal of underscoring the importance of such mechanisms in the overall efficacy of anticancer drugs.
    Keywords:  Free radicals; ROS; anticancer drugs; antioxidants; cancer; oxidative stress; pro-oxidants; redox homeostasis; review
    DOI:  https://doi.org/10.21873/anticanres.15408
  17. Front Oncol. 2021 ;11 761107
    Targeting the Tumor Microenvironment: A Literature Review of the Novel Anti-Tumor Mechanism of Statins.
    Peng-Fei Zhu, Ming-Xing Wang, Zhe-Ling Chen, Liu Yang.
      Statins is widely used in clinical practice as lipid-lowering drugs and has been proven to be effective in the treatment of cardiovascular, endocrine, metabolic syndrome and other diseases. The latest preclinical evidence shows that statins have anti-proliferation, pro-apoptotic, anti-invasion and radiotherapy sensitization effects on tumor cells, suggesting that statins may become a new type of anti-tumor drugs. For a long time, mevalonate pathway has been proved to play a supporting role in the development of tumor cells. As an effective inhibitor of mevalonate pathway, statins have been proved to have a direct auxiliary anti-tumor effect in a large number of studies. In addition, anti-tumor effects of statins through ferroptosis, pyroptosis, autophagy and tumor microenvironment (TME) have also been gradually discovered. However, the specific mechanism of the antitumor effect of statins in the tumor microenvironment has not been clearly elucidated. Herein, we reviewed the antitumor effects of statins in tumor microenvironment, focusing on hypoxia microenvironment, immune microenvironment, metabolic microenvironment, acid microenvironment and mechanical microenvironment.
    Keywords:  HMG-CoA; autophagy; ferroptosis; pyroptosis; statin; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.761107
  18. Acta Biochim Pol. 2021 Nov 15. 68(4): 493-497
    Vitamin D endocrine system in breast cancer.
    Kinga Linowiecka, Agnieszka Wolnicka-Głubisz, Anna A Brożyna.
      Vitamin D is a steroid hormone of great importance in the human body. It is produced in the skin from 7-dehydrocholesterol, upon UV radiation. In order to exert its functions, vitamin D has to be hydroxylated (via CYP27A1 and CYP27B1 hydroxylases), which is followed by its interaction with the vitamin D receptor (VDR) or retinoic acid-related orphan receptors α or γ (RORα and RORγ). By binding with the vitamin D response elements (VDRE) located in the promoter regions, the vitamin D ligand-receptor complex may regulate vitamin D-related genes. Recently, vitamin D has acquired a great interest for its plausible association with cancer development. This review discusses the potential role of vitamin D, its analogues, and enzymes involved in its metabolism with breast cancer incidence and outcome. According to the literature, alterations in the vitamin D endocrine system, both at the mRNA and protein level, have an impact on breast cancer incidence and prognosis. Moreover, specific enzymes participating in vitamin D metabolism may serve as therapeutic targets. Notably, treatment with vitamin D analogues also gives promising results in experimental research. However, given the fact that breast cancer is heterogenous disease, further studies are needed to thoroughly elucidate the potential of vitamin D and enzymes involved in its metabolism in breast cancer development, progression and therapy. Therefore, plausible effects of vitamin D in cancer therapy or prevention have been the principal aim of numerous studies.
    DOI:  https://doi.org/10.18388/abp.2020_5961
  19. Nanomedicine (Lond). 2021 Dec 02.
    Recent advances in targeted nanotherapeutic approaches for breast cancer management.
    Priya Gupta, Yub Raj Neupane, Suhel Parvez, Kanchan Kohli.
      Breast cancer is the most commonly occurring tumor disease worldwide. Breast cancer is currently managed by conventional chemotherapy, which is inadequate in curbing this heterogeneous disease and results in off-site toxic effects, suggesting effective treatment approaches with better therapeutic profiles are needed. This review, therefore, focuses on the recent advancements in delivering therapeutics to the target site using passive and/or active targeted nanodrug-delivery systems to ameliorate endolysosomal escape. In addition, recent strategies in targeting breast cancer stem cells are discussed. The role of naturally cell-secreted nanovesicles (exosomes) in the management of triple-negative breast cancer is also discussed.
    Keywords:  breast cancer; breast cancer stem cells; endolysosomal escape; exosomes; nanomedicine; triple-negative breast cancer
    DOI:  https://doi.org/10.2217/nnm-2021-0281
  20. Nutr Cancer. 2021 Nov 28. 1-12
    Molecular Mechanisms of Cancer Prevention by Gooseberry (Phyllanthus emblica).
    Gaurav Kumar, Venkateshwar Madka, Gopal Pathuri, Vishal Ganta, Chinthalapally V Rao.
      Indian gooseberry (Emblica officinalis Gaertn or Phyllanthus emblica Linn; family Phyllanthaceae) has a recognized history in Indian traditional medicine (Ayurveda). Various therapeutic properties have been attributed to gooseberry as a dietary supplement. Many parts of the plant (fruits, seed, leaves, root, bark, and flowers) possess various activities and are used to treat a range of diseases. This review focuses on the evidence for the cancer-preventive properties of gooseberry, its extracts, and its principal phytochemicals based on studies In Vitro and In Vivo. Most importantly, in multiple rodent models of cancer, treatment with P. emblica was found to prevent tumor incidence, number, and volume at various organ sites. The mechanism(s) implicated in gooseberry-mediated cancer inhibition are diverse and include antioxidants, Phase I and II enzyme modifications, anti-inflammatory action, regulation of the cell cycle, and modulation of oncogenic signaling genes. Studies in humans also indicate that P. emblica can offer various health benefits and synergize with other treatments. This review provides detailed information on the potential use of gooseberry extract as an anticarcinogenic in humans, illuminates the therapeutic applications, and discusses clinical trials.
    DOI:  https://doi.org/10.1080/01635581.2021.2008988
  21. Front Genet. 2021 ;12 758733
    Role of Flavonoids as Epigenetic Modulators in Cancer Prevention and Therapy.
    Nishat Fatima, Syed Shabihe Raza Baqri, Atrayee Bhattacharya, Nii Koney-Kwaku Koney, Kazim Husain, Ata Abbas, Rais A Ansari.
      Epigenetic regulation involves reversible changes in histones and DNA modifications that can be inherited without any changes in the DNA sequence. Dysregulation of normal epigenetic processes can lead to aberrant gene expression as observed in many diseases, notably cancer. Recent insights into the mechanisms of DNA methylation, histone modifications, and non-coding RNAs involved in altered gene expression profiles of tumor cells have caused a paradigm shift in the diagnostic and therapeutic approaches towards cancer. There has been a surge in search for compounds that could modulate the altered epigenetic landscape of tumor cells, and to exploit their therapeutic potential against cancers. Flavonoids are naturally occurring phenol compounds which are abundantly found among phytochemicals and have potentials to modulate epigenetic processes. Knowledge of the precise flavonoid-mediated epigenetic alterations is needed for the development of epigenetics drugs and combinatorial therapeutic approaches against cancers. This review is aimed to comprehensively explore the epigenetic modulations of flavonoids and their anti-tumor activities.
    Keywords:  DNA methylation; cancer; epigenetics; flavonoids; histone modifications; non-coding RNAs
    DOI:  https://doi.org/10.3389/fgene.2021.758733
  22. Drug Dev Res. 2021 Dec 03.
    Platycodin D inhibits the malignant progression of papillary thyroid carcinoma by NF-κB and enhances the therapeutic efficacy of pembrolizumab.
    Bin Deng, Mingyu Sun.
      Papillary thyroid carcinoma (PTC) is the most common pathological type of thyroid cancer. Studies have shown that platycodin D has several pharmacological effects like anti-inflammatory, immunomodulatory, and anti-tumor effects, while the effect and mechanism of platycodin D on PTC are still unclear. This study was designed to investigate the effects of platycodin D on PTC by a series of in vitro and in vivo experiments. The results revealed that platycodin D inhibits PTC cell viability and clonal levels and affects PTC cell cycle. Platycodin D promotes apoptosis in PTC cells. Furthermore, it inhibits the activation of NF-κB signaling pathway and affects cell growth. Platycodin D inhibits PD-L1 expression and enhances the effect of pembrolizumab on PTC cells. In conclusion, platycodin D can effectively block the progression of PTC through the NF-κB signaling pathway, accompanied by cell cycle arrest and enhanced cell apoptosis. In vitro and in vivo, platycodin D was shown to enhance pembrolizumab's sensitivity to PTC. Platycodin D is a promising monomer for therapy of PTC, providing references for future research on PTC treatment.
    Keywords:  NF-κB signaling pathway; papillary thyroid carcinoma; pembrolizumab; platycodin D
    DOI:  https://doi.org/10.1002/ddr.21902
  23. Anticancer Res. 2021 Dec;41(12): 6051-6059
    Evaluation of Erastin as a Therapeutic Agent Under Hypoxic Conditions in Pancreatic Cancer Cells.
    Satoshi Owada, Hitoshi Endo, Yukari Shida, Takaaki Kinoue, Hiroyuki Furuya, Masayuki Tatemichi.
       BACKGROUND/AIM: In pancreatic cancer tissues, hypoxic areas exist due to poor blood flow. Attenuation of the pharmacological efficacy of existing anticancer drugs in these hypoxic areas necessitates the search for novel anticancer compounds. We aimed to determine whether erastin exhibits anticancer effects in a hypoxic environment.
    MATERIALS AND METHODS: Pancreatic cancer cell lines were subjected to cobalt chloride, a hypoxia-mimicking agent. Cell viability assay, measurement of reactive oxygen species, and western blotting analysis were conducted to investigate the efficacy of erastin under hypoxic environments.
    RESULTS: Erastin exhibited remarkable cytotoxicity and induced apoptosis under hypoxic conditions. Furthermore, erastin triggered the intracellular accumulation of reactive oxygen species in a hypoxic environment. Subsequent treatment with N-acetylcysteine, an antioxidant, markedly attenuated cytotoxicity, and apoptosis.
    CONCLUSION: Erastin induces cell death by accumulation of intracellular reactive oxygen species and inducing apoptosis under hypoxic conditions, proving its potential for further development as a novel anticancer compound.
    Keywords:  Apoptosis; erastin; hypoxia; pancreatic cancer; reactive oxygen species
    DOI:  https://doi.org/10.21873/anticanres.15424
  24. Trends Cancer. 2021 Nov 26. pii: S2405-8033(21)00225-9. [Epub ahead of print]
    Redrawing therapeutic boundaries: microbiota and cancer.
    Jonathan Sholl, Gregory D Sepich-Poore, Rob Knight, Thomas Pradeu.
      The unexpected roles of the microbiota in cancer challenge explanations of carcinogenesis that focus on tumor-intrinsic properties. Most tumors contain bacteria and viruses, and the host's proximal and distal microbiota influence both cancer incidence and therapeutic responsiveness. Continuing the history of cancer-microbe research, these findings raise a key question: to what extent is the microbiota relevant for clinical oncology? We approach this by critically evaluating three issues: how the microbiota provides a predictive biomarker of cancer growth and therapeutic responsiveness, the microbiota's causal role(s) in cancer development, and how therapeutic manipulations of the microbiota improve patient outcomes in cancer. Clarifying the conceptual and empirical aspects of the cancer-associated microbiota can orient future research and guide its implementation in clinical oncology.
    Keywords:  biomarkers; cancer; causality; microbiota; network medicine; therapeutic modulation
    DOI:  https://doi.org/10.1016/j.trecan.2021.10.008
  25. ACS Nano. 2021 Dec 01.
    Precise Chemodynamic Therapy of Cancer by Trifunctional Bacterium-Based Nanozymes.
    Weiyun Zhang, Jiawei Liu, Xuyu Li, Yue Zheng, Lianfu Chen, Dongdong Wang, Mohamed Frahat Foda, Zhaoyu Ma, Yanli Zhao, Heyou Han.
      Chemodynamic therapy (CDT) destroys cancer cells by converting H2O2 or O2 into reactive oxygen species (ROS), but its therapeutic efficacy is restricted by the antioxidant capacity of tumor. Previous solutions focused on strengthening the nanodrugs with the ability to increase ROS production or weaken the antioxidant capacity of cancer cells. Conversely, we here develop a mild nanodrug with negligible side effects. Specifically, the Au@Pt nanozyme decorated on a bacterial surface (Bac-Au@Pt) is reported to achieve precise CDT. Due to the tumor targeting ability of bacteria and catalytic property of Au@Pt nanozyme under acidic conditions, this nanosystem can release ROS to tumor cells effectively. In addition, the interferon gamma released by T cells specifically decreases the intracellular reductants in tumor cells, while having no obvious effect on normal cells. Therefore, a low dose of Bac-Au@Pt achieves a satisfactory therapeutic efficacy to tumor cells and is nontoxic to normal cells even at their acidic components. This nanosystem enables CDT and immunotherapy to mutually benefit and improve by each other, providing a promising strategy to achieve high anticancer efficacy even with a low dose usage.
    Keywords:  ferroptosis; immunotherapy; microbial synthesis; nanozyme; precise chemodynamic therapy
    DOI:  https://doi.org/10.1021/acsnano.1c05605
  26. Clin Transl Med. 2021 11;11(11): e578
    Repurposing hyperpolarization-activated cyclic nucleotide-gated channels as a novel therapy for breast cancer.
    Ka-Chun Mok, Ho Tsoi, Ellen Ps Man, Man-Hong Leung, Ka Man Chau, Lai-San Wong, Wing-Lok Chan, Sum-Yin Chan, Mai-Yee Luk, Jessie Y W Chan, Jackie K M Leung, Yolanda H Y Chan, Sellma Batalha, Virginia Lau, David C W Siu, Terence K W Lee, Chun Gong, Ui-Soon Khoo.
      Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are members of the voltage-gated cation channel family known to be expressed in the heart and central nervous system. Ivabradine, a small molecule HCN channel-blocker, is FDA-approved for clinical use as a heart rate-reducing agent. We found that HCN2 and HCN3 are overexpressed in breast cancer cells compared with normal breast epithelia, and the high expression of HCN2 and HCN3 is associated with poorer survival in breast cancer patients. Inhibition of HCN by Ivabradine or by RNAi, aborted breast cancer cell proliferation in vitro and suppressed tumour growth in patient-derived tumour xenograft models established from triple-negative breast cancer (TNBC) tissues, with no evident side-effects on the mice. Transcriptome-wide analysis showed enrichment for cholesterol metabolism and biosynthesis as well as lipid metabolism pathways associated with ER-stress following Ivabradine treatment. Mechanistic studies confirmed that HCN inhibition leads to ER-stress, in part due to disturbed Ca2+ homeostasis, which subsequently triggered the apoptosis cascade. More importantly, we investigated the synergistic effect of Ivabradine and paclitaxel on TNBC and confirmed that both drugs acted synergistically in vitro through ER-stress to amplify signals for caspase activation. Combination therapy could suppress tumour growth of xenografts at much lower doses for both drugs. In summary, our study identified a new molecular target with potential for being developed into targeted therapy, providing scientific grounds for initiating clinical trials for a new treatment regimen of combining HCN inhibition with chemotherapy.
    Keywords:  ER-stress; HCN; Ivabradine; targeted therapy; triple-negative breast cancer
    DOI:  https://doi.org/10.1002/ctm2.578
  27. J Exp Clin Cancer Res. 2021 Nov 29. 40(1): 374
    Hydroxychloroquine synergizes with the PI3K inhibitor BKM120 to exhibit antitumor efficacy independent of autophagy.
    Xin Peng, Shaolu Zhang, Wenhui Jiao, Zhenxing Zhong, Yuqi Yang, Francois X Claret, Moshe Elkabets, Feng Wang, Ran Wang, Yuxu Zhong, Zhe-Sheng Chen, Dexin Kong.
       BACKGROUND: The critical role of phosphoinositide 3-kinase (PI3K) activation in tumor cell biology has prompted massive efforts to develop PI3K inhibitors (PI3Kis) for cancer therapy. However, recent results from clinical trials have shown only a modest therapeutic efficacy of single-agent PI3Kis in solid tumors. Targeting autophagy has controversial context-dependent effects in cancer treatment. As a FDA-approved lysosomotropic agent, hydroxychloroquine (HCQ) has been well tested as an autophagy inhibitor in preclinical models. Here, we elucidated the novel mechanism of HCQ alone or in combination with PI3Ki BKM120 in the treatment of cancer.
    METHODS: The antitumor effects of HCQ and BKM120 on three different types of tumor cells were assessed by in vitro PrestoBlue assay, colony formation assay and in vivo zebrafish and nude mouse xenograft models. The involved molecular mechanisms were investigated by MDC staining, LC3 puncta formation assay, immunofluorescent assay, flow cytometric analysis of apoptosis and ROS, qRT-PCR, Western blot, comet assay, homologous recombination (HR) assay and immunohistochemical staining.
    RESULTS: HCQ significantly sensitized cancer cells to BKM120 in vitro and in vivo. Interestingly, the sensitization mediated by HCQ could not be phenocopied by treatment with other autophagy inhibitors (Spautin-1, 3-MA and bafilomycin A1) or knockdown of the essential autophagy genes Atg5/Atg7, suggesting that the sensitizing effect might be mediated independent of autophagy status. Mechanistically, HCQ induced ROS production and activated the transcription factor NRF2. In contrast, BKM120 prevented the elimination of ROS by inactivation of NRF2, leading to accumulation of DNA damage. In addition, HCQ activated ATM to enhance HR repair, a high-fidelity repair for DNA double-strand breaks (DSBs) in cells, while BKM120 inhibited HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51.
    CONCLUSIONS: Our study revealed that HCQ and BKM120 synergistically increased DSBs in tumor cells and therefore augmented apoptosis, resulting in enhanced antitumor efficacy. Our findings provide a new insight into how HCQ exhibits antitumor efficacy and synergizes with PI3Ki BKM120, and warn that one should consider the "off target" effects of HCQ when used as autophagy inhibitor in the clinical treatment of cancer.
    Keywords:  Autophagy; BKM120; Homologous recombination repair; Hydroxychloroquine; NRF2; PI3K; ROS
    DOI:  https://doi.org/10.1186/s13046-021-02176-2
  28. Mater Horiz. 2021 Aug 01. 8(8): 2216-2229
    PSMA-targeted arsenic nanosheets: a platform for prostate cancer therapy via ferroptosis and ATM deficiency-triggered chemosensitization.
    Hui Wang, Li Zhang, Zhaohua Miao, Meng Zhang, Hang Liu, Qiong He, Jialin Meng, Longping Wen, Zunfu Ke, Zhengbao Zha, Run Lin, Chaozhao Liang.
      Ferroptosis, a newly recognized form of non-apoptotic cell death, has recently been introduced for effective cancer therapy. The reported ferroptosis-inducing nanomaterials mainly consisted of metal-based components. Herein, we designed an inorganic metal-free nanoplatform, PSMA-targeted arsenic nanosheets (PMANs), which simultaneously increased glutathione (GSH) consumption, suppressed solute carrier family 7 member 11 (SLC7A11) and glutathione-dependent peroxidase 4 (GPX4) expression, and promoted the generation of reactive oxygen species (ROS) and lipid peroxides (LPO). In addition, owing to the large surface area, PMANs efficiently transported doxorubicin (DOX) to prostate cancer for synergistic therapy. Surprisingly, we found that PMANs could sensitize prostate cancer cells to DOX through downregulating the expression of ataxia telangiectasia mutated (ATM), which further augmented the GPX4 downregulation-mediated ferroptotic tumoricidal effect. Given that arsenic trioxide has been routinely and successfully used in the clinical treatment of leukemia for a long time, we anticipate that PMANs will offer a promising strategy for prostate cancer therapy.
    DOI:  https://doi.org/10.1039/d0mh01992e
  29. Front Pharmacol. 2021 ;12 685773
    Identifying the Effect of Ursolic Acid Against Triple-Negative Breast Cancer: Coupling Network Pharmacology With Experiments Verification.
    Yubao Zhang, Xiaoran Ma, Huayao Li, Jing Zhuang, Fubin Feng, Lijuan Liu, Cun Liu, Changgang Sun.
      Triple negative breast cancer (TNBC) is a subtype of breast cancer with complex heterogeneity, high invasiveness, and long-term poor prognosis. With the development of molecular pathology and molecular genetics, the gene map of TNBC with distinctive biological characteristics has been outlined more clearly. Natural plant extracts such as paclitaxel, vinblastine, colchicine etc., have occupied an important position in the treatment of hormone-independent breast cancer. Ursolic acid (UA), a triterpenoid acid compound derived from apple, pear, loquat leaves, etc., has been reported to be effective in a variety of cancer treatments, but there are few reports on the treatment of TNBC. This study performed comprehensive bioinformatics analysis and in vitro experiments to identify the effect of UA on TNBC treatment and its potential molecular mechanism. Our results showed that UA could not only reduce the proliferation, migration, and invasion in MDA-MB-231 and MDA-MB-468 cell lines with a dose-dependent manner but also induce cell cycle arrest and apoptosis. Meanwhile, we collected the gene expression data GSE45827 and GSE65194 from GEO for comparison between TNBC and normal cell type and obtained 724 DEGs. Subsequently, PLK1 and CCNB1 related to TNBC were screened as the key targets via topological analysis and molecular docking, and gene set enrichment analysis identified the key pathway as the p53 signaling pathway. In addition, quantitative real-time PCR and western blot verified the key genes were PLK1 and CCNB1. In vivo and in vitro experiments showed that UA could inhibit the growth of TNBC cells, and down-regulate the protein expression levels of PLK1 and CCNB1 by mediating p53 signaling pathway. These findings provide strong evidence for UA intervention in TNBC via multi-target therapy.
    Keywords:  antiproliferative; molecular docking; network pharmacology; triple-negative breast cancer; ursolic acid
    DOI:  https://doi.org/10.3389/fphar.2021.685773
  30. J Colloid Interface Sci. 2021 Nov 22. pii: S0021-9797(21)02017-8. [Epub ahead of print]
    Periodic mesoporous organosilica coupled with chlorin e6 and catalase for enhanced photodynamic therapy to treat triple-negative breast cancer.
    Wei Tian, Shouju Wang, Ying Tian, Xiaodan Su, Hui Sun, Yuxia Tang, Guangming Lu, Sheng Liu, Haibin Shi.
      Photodynamic therapy (PDT) has become a promising treatment option for highly aggressive triple-negative breast cancer (TNBC); however, hypoxia limits the efficacy of PDT and promotes tumour aggression. In this work, we first constructed a multifunctional yolk-shell structured nanoplatform consisting of periodic mesoporous organosilica (PMO) coupled with chlorin e6 (Ce6) and catalase (Catalase) (Yolk-Shell PMO-Ce6@Catalase) for enhanced PDT against TNBC. This nanoplatform has an organic-inorganic hybrid skeleton structure, a uniform size and good stability and biocompatibility. In vitro experiments showed that the nanoplatform has a good ability to generate singlet oxygen. Catalase can convert H2O2 into O2, increasing the concentration of oxygen around the cells and overcoming the problem of hypoxia in the tumour, which enhances the effects of PDT. The in vivo experimental results showed that PDT with the Yolk-Shell PMO-Ce6@Catalase nanoplatform, compared with free Ce6 and Yolk-Shell PMO-Ce6 PDT, can significantly inhibit tumour growth, revealing the most extensive cellular apoptosis and necrosis in the tumour area in this treatment group. Additionally, the histopathological results showed that PDT did not cause significant side effects to the major organs. Therefore, we believe that this Yolk-Shell PMO-Ce6@Catalase nanoplatform has excellent clinical potential for PDT against TNBC.
    Keywords:  Catalase; Chlorin e6; Periodic mesoporous organosilica; Photodynamic therapy; Triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.jcis.2021.11.107
  31. Biomater Sci. 2021 Dec 01.
    Multifunctional FeS2@SRF@BSA nanoplatform for chemo-combined photothermal enhanced photodynamic/chemodynamic combination therapy.
    Miao Feng, Meiting Li, Rui Dai, Shuting Xiao, Junjie Tang, Xiaoge Zhang, Baizhu Chen, Jie Liu.
      Combination therapy has been widely studied due to its promising applications in tumor therapy. However, a sophisticated nanoplatform and sequential irradiation with different laser sources for phototherapy complicate the treatment process. Unlike the integration of therapeutic agents, we report a FeS2@SRF@BSA nanoplatform for the combination of chemo-combined photothermal therapy (PTT) enhanced photodynamic therapy (PDT) and chemodynamic therapy (CDT) to achieve an "all-in-one" therapeutic agent. Ultrasmall FeS2 nanoparticles (NPs) with a size of 7 nm exhibited higher Fenton reaction rates due to their large specific surface areas. A photodynamic reaction could be triggered and could generate 1O2 to achieve PDT under 808 nm irradiation. FeS2 NPs also exhibited the desired photothermal properties under the same wavelength of the laser. The Fenton reaction and photodynamic reaction were both significantly improved to accumulate more reactive oxygen species (ROS) with an increase of temperature under laser irradiation. Besides, loading of the chemotherapeutic drug sorafenib (SRF) further improved the efficacy of tumor treatment. To realize long blood circulation, bovine serum albumin (BSA) was used as a carrier to encapsulate FeS2 NPs and SRF, remarkably improving the biocompatibility and tumor enrichment ability of the nanomaterials. Additionally, the tumors on mice treated with FeS2@SRF@BSA almost disappeared under 808 nm irradiation. To sum up, FeS2@SRF@BSA NPs possess good biocompatibility, stability, and sufficient therapeutic efficacy in combination therapy for cancer treatment. Our study pointed out a smart design of the nanoplatform as a multifunctional therapeutic agent for combination cancer therapy in the near future.
    DOI:  https://doi.org/10.1039/d1bm01597d
  32. ACS Appl Mater Interfaces. 2021 Dec 02.
    Plasmon-Triggered Upconversion Emissions and Hot Carrier Injection for Combinatorial Photothermal and Photodynamic Cancer Therapy.
    Subin Yu, Dohyub Jang, Hong Yuan, Wen-Tse Huang, Minju Kim, Filipe Marques Mota, Ru-Shi Liu, Hyukjin Lee, Sehoon Kim, Dong Ha Kim.
      Despite the unique ability of lanthanide-doped upconversion nanoparticles (UCNPs) to convert near-infrared (NIR) light to high-energy UV-vis radiation, low quantum efficiency has rendered their application unpractical in biomedical fields. Here, we report anatase titania-coated plasmonic gold nanorods decorated with UCNPs (Au NR@aTiO2@UCNPs) for combinational photothermal and photodynamic therapy to treat cancer. Our novel architecture employs the incorporation of an anatase titanium dioxide (aTiO2) photosensitizer as a spacer and exploits the localized surface plasmon resonance (LSPR) properties of the Au core. The LSPR-derived near-field enhancement induces a threefold boost of upconversion emissions, which are re-absorbed by neighboring aTiO2 and Au nanocomponents. Photocatalytic experiments strongly infer that LSPR-induced hot electrons are injected into the conduction band of aTiO2, generating reactive oxygen species. As phototherapeutic agents, our hybrid nanostructures show remarkable in vitro anticancer effect under NIR light [28.0% cancer cell viability against Au NR@aTiO2 (77.3%) and UCNP@aTiO2 (98.8%)] ascribed to the efficient radical formation and LSPR-induced heat generation, with cancer cell death primarily following an apoptotic pathway. In vivo animal studies further confirm the tumor suppression ability of Au NR@aTiO2@UCNPs through combinatorial photothermal and photodynamic effect. Our hybrid nanomaterials emerge as excellent multifunctional phototherapy agents, providing a valuable addition to light-triggered cancer treatments in deep tissue.
    Keywords:  localized surface plasmon resonance; photosensitizer; phototherapy; titanium dioxide; upconversion
    DOI:  https://doi.org/10.1021/acsami.1c21949
  33. J Thromb Haemost. 2021 Nov 30.
    Factor VIII as a potential player in cancer pathophysiology.
    Gillian E Walker, Simone Merlin, Diego Zanolini, Andrea Vandoni, Alessandro Volpe, Gianluca Gaidano, Guido Valente, Martina Olivero, Antonia Follenzi.
       BACKGROUND: "Trousseau's Sign" was the first demonstration of a close relationship between cancer and thrombosis. Currently, venous thromboembolism (VTE) is 5-6 times more likely to occur in cancer patients, while there is a greater risk of cancer diagnoses following thromboses. In considering novel players, factor VIII (FVIII), an essential coagulation co-factor with emerging extra-coagulative functions, has been identified as an independent VTE risk factor in cancer, however, the basis of this increase is unknown.
    OBJECTIVE: To investigate the possible direct expression and secretion of FVIII by cancer cells.
    METHODS: Bladder cancer, with a high VTE-risk, and normal bladder tissue and epithelium, were used to investigate FVIII. Factor VIII protein and secretion were examined in bladder cancer cell lines. Expanding to other cancers, the Cancer Cell line Encyclopedia (CCLE) database was used to analyze FVIII, Tissue Factor (TF), FV, FVII, FIX, FX and von Willebrand factor (vWF) mRNA in 811 cell lines subdivided according to origin. Factor VIII protein synthesis, secretion and bioactivity were investigated in a profile of cancer cell lines of differing origins.
    RESULTS AND CONCLUSIONS: While expressed in the normal bladder epithelium, FVIII mRNA and protein were higher in matched bladder neoplasms, with synthesis and secretion of bioactive FVIII evident in bladder cancer cells. This can be extended to other cancer cell lines, with a pattern reflecting the tumor origin, and which is independent of vWF and other relevant players in the coagulation cascade. Herein, evidence is provided of a possible independent role for FVIII in cancer-related pathophysiology.
    Keywords:  Factor VIII; cancer; expression; secretion; thrombosis
    DOI:  https://doi.org/10.1111/jth.15611
  34. Nano Converg. 2021 Nov 30. 8(1): 38
    Quantifying and controlling bond multivalency for advanced nanoparticle targeting to cells.
    Elliot Y Makhani, Ailin Zhang, Jered B Haun.
      Nanoparticles have drawn intense interest as delivery agents for diagnosing and treating various cancers. Much of the early success was driven by passive targeting mechanisms such as the enhanced permeability and retention (EPR) effect, but this has failed to lead to the expected clinical successes. Active targeting involves binding interactions between the nanoparticle and cancer cells, which promotes tumor cell-specific accumulation and internalization. Furthermore, nanoparticles are large enough to facilitate multiple bond formation, which can improve adhesive properties substantially in comparison to the single bond case. While multivalent binding is universally believed to be an attribute of nanoparticles, it is a complex process that is still poorly understood and difficult to control. In this review, we will first discuss experimental studies that have elucidated roles for parameters such as nanoparticle size and shape, targeting ligand and target receptor densities, and monovalent binding kinetics on multivalent nanoparticle adhesion efficiency and cellular internalization. Although such experimental studies are very insightful, information is limited and confounded by numerous differences across experimental systems. Thus, we focus the second part of the review on theoretical aspects of binding, including kinetics, biomechanics, and transport physics. Finally, we discuss various computational and simulation studies of nanoparticle adhesion, including advanced treatments that compare directly to experimental results. Future work will ideally continue to combine experimental data and advanced computational studies to extend our knowledge of multivalent adhesion, as well as design the most powerful nanoparticle-based agents to treat cancer.
    Keywords:  Bond biophysics; Multivalent adhesions; Nanoparticle; Simulation; Targeting
    DOI:  https://doi.org/10.1186/s40580-021-00288-1
  35. Adv Mater. 2021 Dec 02. e2107009
    Metal-Phenolic Network-Coated Dendrimer-Drug Conjugates for Tumor MR Imaging and Chemo/Chemodynamic Therapy via Amplification of Endoplasmic Reticulum Stress.
    Zhiqiang Wang, Yunqi Guo, Yu Fan, Jingwen Chen, Han Wang, Mingwu Shen, Xiangyang Shi.
      Amplification of endoplasmic reticulum stress (ERS) to realize enhanced cancer therapy has been considered to be unique in current cancer nanomedicine design. Herein, we report the design of metal-phenolic network-coated dendrimer-drug conjugates as a novel theranostic nanoplatform based on ERS amplification. In our design, acetylated generation 5 poly(amidoamine) dendrimers were conjugated with an ERS drug toyocamycin (Toy) through the attached phenylboronic acid moiety, and coated with iron (Fe)-tannic acid (TF) network. The generated nanocomplexes with a size of 50.2 nm are stable under a physiological environment, and can rapidly release Toy under the tumor microenvironment due to the pH- and reactive oxygen species-responsive boronic ester bonds to effectively inhibit the ERS-mediated cancer cell adaptation. Meanwhile, the coated TF network enables the nanocomplexes to generate cytotoxic hydroxyl radicals through a Fenton reaction, amplifying the ERS for improved chemotherapy/chemodynamic therapy of cancer cells in vitro and a xenografted breast tumor model in vivo. Moreover, the coating of TF also renders the complexes with an eminent r1 relaxivity for in vivo T1 -weighted tumor magnetic resonance imaging. The created intelligent nanocomplexes may represent an advanced nanomedicine formulation uniquely integrated with metal-phenolic network and dendrimer nanotechnology for imaging-guided cancer therapy through ERS amplification. This article is protected by copyright. All rights reserved.
    Keywords:  amplification of endoplasmic reticulum stress; chemo/chemodynamic therapy; dendrimer; iron-tannic acid network; toyocamycin
    DOI:  https://doi.org/10.1002/adma.202107009
  36. Curr Opin Endocrinol Diabetes Obes. 2021 Nov 26.
    An Update on Vitamin D Deficiency in the twenty-first century: nature and nurture.
    Ashley J Stoffers, David R Weber, Michael A Levine.
       PURPOSE OF REVIEW: Here, we review the most up-to-date understanding of the pathogenesis, prevention and treatment of vitamin D deficient rickets in children. This will include recent advances in the genetic determinants of abnormal vitamin D metabolism, with the intention of aiding clinicians with establishing the diagnosis and implementing treatment plans for children presenting with vitamin D deficiency rickets.
    RECENT FINDINGS: Vitamin D deficiency rickets is a frequently encountered, but entirely preventable, disorder of bone mineral metabolism. Risk factors for developing vitamin D deficiency rickets include inadequate exposure to sunlight, exclusive breast feeding without vitamin D supplementation and inadequate intake of vitamin D, calcium or phosphorus. Other factors that may influence the development of vitamin D deficiency and/or rickets include genetic alterations or medications that alter vitamin D metabolism.
    SUMMARY: Vitamin D levels in individuals are influenced by environmental factors, as well as genetic factors. A thorough understanding of these factors is critical for the evaluation and treatment of a child presenting with rickets. There remains a great need for additional research to determine ideal vitamin D status across diverse populations, and to better understand how vitamin D status affects overall health.
    DOI:  https://doi.org/10.1097/MED.0000000000000691
  37. Front Bioeng Biotechnol. 2021 ;9 752982
    Biocompatible Mesoporous Silica-Polydopamine Nanocomplexes as MR/Fluorescence Imaging Agent for Light-Activated Photothermal-Photodynamic Cancer Therapy In Vivo.
    Jiahui Lu, Chen Ni, Jie Huang, Yawen Liu, Yingkai Tao, Pengcheng Hu, Yong Wang, Shaohui Zheng, Meilin Shi.
      Conventional cancer phototherapy with single modality suffers from low therapeutic efficacy and undesired posttreatment damage for adjacent normal tissues. Therefore, the lower NIR laser irradiation power is vital to the reduction or preclusion of risk of scalds and burns in normal tissues. Herein, we rationally proposed a novel multifunctional nanocomplex, which enabled good magnetic resonance (MR) imaging contrast effect and promising photothermal conversion efficacy. The prepared core/shell nanocomplexes [MSN-Ce6@PDA (Mn)] were composed of chlorin e6-embedded mesoporous silica/nanoparticle composites as the cores, and then polydopamine and manganese ions were conjugated on the cores to form protective shells. The MSN-Ce6@PDA (Mn) nanocomplexes revealed superior properties in colloidal stability, photothermal conversion, reaction oxygen species generation, magnetic resonance imaging, etc. Under the guidance of MR and fluorescence imaging, these MSN-Ce6@PDA (Mn) nanocomplexes were found to be primarily accumulated in the MDA-MB-231 tumor area. Furthermore, the combined photodynamic and photothermal therapy exhibited strong inhibition to the growth of MDA-MB-231 tumor in vitro and in vivo. Besides, the MSN-Ce6@PDA (Mn) nanocomplexes also exhibited excellent biocompatibility and low damage to the healthy animals. Hence, the results demonstrated that the prepared MSN-Ce6@PDA (Mn) nanocomplex would be a promising potential for multimodal imaging-guided phototherapy.
    Keywords:  chlorin e6; core shell nanoparticles; fluorescence imaging (FI); magnetic resonance imaging; photodynamic theraphy; photothermal therapy
    DOI:  https://doi.org/10.3389/fbioe.2021.752982
  38. Curr Med Chem. 2021 Nov 29.
    Oligonucleotides carrying nucleoside antimetabolites as potential prodrugs.
    Carme Fàbrega, Anna Clua, Ramon Eritja, Anna Aviñó.
       BACKGROUND: Nucleoside and nucleobase antimetabolites are an important class of chemotherapeutic agents for the treatment of cancer as well as other diseases.
    INTRODUCTION: In order to avoid undesirable side effects, several prodrug strategies have been developed for that purpose. In the present review, we describe a relatively unknown strategy that consists in the use of oligonucleotides modified with nucleoside antimetabolites as prodrugs.
    METHOD: The active nucleotides are generated by enzymatic degradation once incorporated into cells. This strategy has attracted large interest and is very active at present due to the continuous developments made on therapeutic oligonucleotides and the recent advances in the field of nanomaterials and nanomedicine.
    RESULTS: A large research effort was done mainly in the improvement of the antiproliferative properties of nucleoside homopolymers, but recently, chemically modified aptamers, antisense oligonucleotides and/or siRNA carrying antiproliferative nucleotides have demonstrated a great potential due to the synergetic effect of both therapeutic entities. In addition, DNA nanostructures with interesting properties have been built to combine antimetabolites and enhancers of cellular uptake in the same scaffold. Finally, protein nanoparticles functionalized with receptor-binders and antiproliferative oligomers represent a new avenue for a more effective treatment in cancer therapy.
    CONCLUSION: It is expected that oligonucleotides carrying nucleoside antimetabolites will be considered as potential drugs in the near future for biomedical applications.
    Keywords:  antimetabolites; antiproliferative oligomers; cytarabine; floxuridine; gemcitabine; homopolymers; nanomedicine; nucleosides
    DOI:  https://doi.org/10.2174/0929867328666211129124039
  39. BMC Med Genomics. 2021 Dec 01. 14(1): 284
    Rare and potentially pathogenic variants in hydroxycarboxylic acid receptor genes identified in breast cancer cases.
    Cierla McGuire Sams, Kasey Shepp, Jada Pugh, Madison R Bishop, Nancy D Merner.
       BACKGROUND: Three genes clustered together on chromosome 12 comprise a group of hydroxycarboxylic acid receptors (HCARs): HCAR1, HCAR2, and HCAR3. These paralogous genes encode different G-protein coupled receptors responsible for detecting glycolytic metabolites and controlling fatty acid oxidation. Though better known for regulating lipid metabolism in adipocytes, more recently, HCARs have been functionally associated with breast cancer proliferation/survival; HCAR2 has been described as a tumor suppressor and HCAR1 and HCAR3 as oncogenes. Thus, we sought to identify germline variants in HCAR1, HCAR2, and HCAR3 that could potentially be associated with breast cancer risk.
    METHODS: Two different cohorts of breast cancer cases were investigated, the Alabama Hereditary Cancer Cohort and The Cancer Genome Atlas, which were analyzed through nested PCRs/Sanger sequencing and whole-exome sequencing, respectively. All datasets were screened for rare, non-synonymous coding variants.
    RESULTS: Variants were identified in both breast cancer cohorts, some of which appeared to be associated with breast cancer BC risk, including HCAR1 c.58C > G (p.P20A), HCAR2 c.424C > T (p.R142W), HCAR2 c.517_518delinsAC (p.G173T), HCAR2 c.1036A > G (p.M346V), HCAR2 c.1086_1090del (p.P363Nfs*26), HCAR3 c.560G > A (p.R187Q), and HCAR3 c.1117delC (p.Q373Kfs*82). Additionally, HCAR2 c.515C > T (p.S172L), a previously identified loss-of-function variant, was identified.
    CONCLUSIONS: Due to the important role of HCARs in breast cancer, it is vital to understand how these genetic variants play a role in breast cancer risk and proliferation and their consequences on treatment strategies. Additional studies will be needed to validate these findings. Nevertheless, the identification of these potentially pathogenic variants supports the need to investigate their functional consequences.
    Keywords:  And protein elongation; Breast cancer; G-protein coupled receptor; Genetic variants; Hydroxycarboxylic acid receptor
    DOI:  https://doi.org/10.1186/s12920-021-01126-3
  40. Evid Based Complement Alternat Med. 2021 ;2021 1448206
    A Metabolomic Investigation of Eugenol on Colorectal Cancer Cell Line HT-29 by Modifying the Expression of APC, p53, and KRAS Genes.
    Elham Ghodousi-Dehnavi, Reza H Hosseini, Mohammad Arjmand, Sima Nasri, Zahra Zamani.
      Colorectal cancer is one of the most lethal cancers with a high mortality rate. Chemotherapy results in drug resistance in some cases; hence, herbal medicines are sometimes used in adjunct with it. Eugenol has been reported to have anti-inflammatory, antioxidant, and anticancer properties. Metabolomics is a study of metabolic changes within an organism using high-throughput technology. The purpose of this research was to investigate the anticancer effects of eugenol and variations in p53, KRAS, and APC gene expression and metabolic changes associated with the abovementioned gene expressions using 1HNMR spectroscopy. The MTT method was used to determine cell viability and its IC50 detected. After treating HT-29 cells with IC50 concentration of eugenol, RNA was extracted and cDNA was obtained from them and the expression of p53, KRAS, and APC genes was measured using the qRT-PCR technique. Metabolites were extracted using the chloroform-ethanol method, lyophilized, and sent for 1HNMR spectroscopy using the 1D-NOESY protocol. Chemometrics analysis such as PLS-DA was performed, and differentiated metabolites were identified using the Human Metabolome Database. Integrated metabolic analysis using the metabolites and gene expression was performed by the MetaboAnalyst website. The observed IC50 for eugenol was 500 μM, and the relative expression of APC and p53 genes in the treated cells increased compared to the control group, and the expression of KRAS oncogene gene decreased significantly. The crucial changes in convergent metabolic phenotype with genes were identified. The results indicate that eugenol exhibits its antitumor properties by targeting a specific biochemical pathway in the cell's metabolome profile due to changes in genes involved in colon cancer.
    DOI:  https://doi.org/10.1155/2021/1448206
  41. ACS Nano. 2021 Dec 01.
    Prussian Blue/Calcium Peroxide Nanocomposites-Mediated Tumor Cell Iron Mineralization for Treatment of Experimental Lung Adenocarcinoma.
    Kaixin Zhang, Jicheng Wu, Xiaoxiong Zhao, Jiale Qin, Yi Xue, Weizeng Zheng, Lixiu Wang, Haoran Wang, Hong Shen, Tianye Niu, Yan Luo, Ruikang Tang, Ben Wang.
      Current lung cancer diagnosis methods encounter delayed visual confirmation of tumor foci and low-resolution metrics in imaging findings, which delays the early treatment of tumors. Here, we developed a potent lung cancer imaging and treatment strategy centered around a nanotransformational concept of tumor iron mineralization in situ, which employs Prussian blue/calcium peroxide nanocomposites as a precursor. The resultant iron mineralization in tumor cells greatly facilitates the early and differential diagnosis of lung carcinoma from benign nodules via medical imaging, meanwhile introducing oxidative stress to activate the cellular apoptosis and ferroptosis pathways, resulting in inhibition of the malignant behavior of tumor cells. Tumor-microenvironment-triggered iron mineralization enables integration of the detection and prevention of tumor metastasis at its early stages with no assistance of toxic drugs, which offers a potential solution for the precise management of lung cancer with ideal outcomes.
    Keywords:  antitumor therapy; biomineralization; differential diagnosis; iron mineralization; lung cancer
    DOI:  https://doi.org/10.1021/acsnano.1c07308
  42. ChemMedChem. 2021 Dec 02.
    Amphiphilic Fullerene-BODIPY Photosensitizers for Targeted Photodynamic Therapy.
    Ezel Öztürk Gündüz, Gürcan Günaydin, Elif Okutan.
      Nanotheranostic tailor-made carriers are potent platforms for the treatment of cancer that propound a number of advantages over conventional agents for photodynamic therapy (PDT). Herein, four new heavy atom free amphiphilic glucose-BODIPY-fullerene dyads ( 14 - 17 ) endowed with carbohydrate moieties in the styryl units, that can also form nanomicelles ( 14 - 17NM) with Tween 80 for PDT are reported. Glucose-BODIPY-fullerene systems ( 14 - 17 ) and related nanomicelles ( 14 - 17NM ) have been prepared to emcee efficient singlet oxygen generation upon light irradiation. In vitro anti-tumor effects of the compounds 14 - 17 and 14 - 17NM in the presence of light and in darkness have been investigated with K562 human chronic myelogenous leukemia suspension cells. Anti-tumor toxicity upon light irradiation was due to the formation of singlet oxygen and reactive oxygen species (ROS). This study may provide an accomplished example of efficient PDT applications based on nanovehicles fabricated with universal spin converter, fullerene, light harvesting unit, BODIPY dyes conjugated with targeting units to fight against cancer.
    Keywords:  BODIPY; MTT assay; PDT; Singlet oxygen; fullerene
    DOI:  https://doi.org/10.1002/cmdc.202100693
  43. Oncotarget. 2021 Nov 23. 12(24): 2388-2403
    Circulating low density neutrophils of breast cancer patients are associated with their worse prognosis due to the impairment of T cell responses.
    Diana P Saraiva, Bruna F Correia, Rute Salvador, Nídia de Sousa, António Jacinto, Sofia Braga, M Guadalupe Cabral.
      Neutrophils are prominent immune components of tumors, having either anti-tumor (N1) or pro-tumor activity (N2). Circulating neutrophils, divided into high density neutrophils (HDN) and low density neutrophils (LDN), functionally mirror those N1 and N2 cells, respectively. LDN are rare in non-pathological conditions, but frequent in cancer, exhibiting a pro-tumor phenotype. These findings have been mainly demonstrated in animal models, thus proper validation in humans is still imperative. Here, we observed that LDN were increased in the blood of breast cancer (BC) patients, particularly with metastatic disease. Within the population of non-metastatic patients, LDN were more prevalent in patients with poor response to neoadjuvant chemotherapy than patients with a good response. The higher incidence of LDN in BC patients with severe disease or resistance to treatment can be explained by their pro-tumor/immunosuppressive characteristics. Moreover, the percentage of LDN in BC patients' blood was negatively correlated with activated cytotoxic T lymphocytes and positively correlated with immunosuppressive regulatory T cells. The ability of LDN to spoil anti-tumor immune responses was further demonstrated ex vivo. Hence, this study reveals the potential of LDN as a biomarker of BC response to treatment and opens new avenues for developing new immunotherapies.
    Keywords:  biomarker; breast cancer; chemotherapy response; low density neutrophils; tumor-associated neutrophils
    DOI:  https://doi.org/10.18632/oncotarget.28135
  44. J Colloid Interface Sci. 2021 Nov 23. pii: S0021-9797(21)02032-4. [Epub ahead of print]
    Construction of tellurium-doped mesoporous bioactive glass nanoparticles for bone cancer therapy by promoting ROS-mediated apoptosis and antibacterial activity.
    Ying Zhang, Meng Hu, Wei Zhang, Xiaona Zhang.
      The commonly used treatment methods for bone cancer include chemotherapy, surgery and radiotherapy, but there are disadvantages such as nonspecific distribution, high toxicity of chemotherapy drugs, implantable infections and low monitoring. Nanoparticles are the new development direction of nanomedicine in cancer treatment. Structural characteristics of nanoparticles make it an excellent model for targeting and penetrating cancer-induced abnormal cell growth. In this study, a kind of novel and interesting tellurium ion doped mesoporous bioactive glasses (Te-MBG) nanoparticles were successfully synthesized by a simple sol-gel method, which had uniform spherical morphology (≈ 500 nm), high surface area (> 300 m2/g) and mesopore volume (> 0.30 cm3/g). Results found that Te doping does not affect the mineralization and degradation of the MBG nanoparticles. Meanwhile, compared to the undoped MBG, Te doped MBG not merely had the ability to promote MG63 cell apoptosis to inhibit bone cancer growth by ROS-mediated, but also had significant antibacterial activity. This all depends on the concentration of Te doping. It can be seen that Te-MBG nanoparticles can not only potentially fill bone defects caused by bone cancer removal, but also induce cancer cell apoptosis by tellurium release inducing reactive oxygen species (ROS) excessive production to inhibit bone cancer formation. This study provides a feasible strategy for the development of Te-MBG nanoparticles as well as their evaluation and basic research for bone cancer therapy.
    Keywords:  Antibacterial activity; Apoptosis; Bone cancer; Nanoparticles; Tellurium
    DOI:  https://doi.org/10.1016/j.jcis.2021.11.122
  45. Epilepsy Res. 2021 Nov 26. pii: S0920-1211(21)00284-9. [Epub ahead of print]178 106829
    Impact of carbamazepine on vitamin D levels: A meta-analysis.
    Carla LoPinto-Khoury, Laura Brennan, Scott Mintzer.
       PURPOSE: There are longstanding concerns about the impact of enzyme-inducing anti-seizure medications (ASMs) on vitamin D, an important molecule in both bone metabolism and inflammation pathways. The relationship between chronic use of carbamazepine and vitamin D levels has been studied, but no comprehensive review to inform practitioners and policymakers is currently available. We performed a meta-analysis on studies that measured 25-hydroxyvitamin D (25OHD) levels in persons taking carbamazepine to determine whether this drug significantly reduces circulating 25OHD.
    PRINCIPAL RESULTS: From a literature search of the terms "carbamazepine" and "vitamin D", we identified 12 studies that measured 25OHD levels in persons on carbamazepine monotherapy groups and controls. Persons taking carbamazepine had significantly lower 25OHD levels than persons not taking carbamazepine. The average 25OHD levels of carbamazepine-treated patients across all studies was 21.8 ng/mL (IQR 15.4,26.0) whereas 25OHD levels of control subjects was 28.0 ng/mL (IQR 20.8,30.4). The weighted difference of means was 4.00 ng/mL of 25OHD. Neither age nor sex nor duration of carbamazepine therapy had a significant impact on this finding. The effect was similar irrespective of whether the comparator group consisted of healthy controls or epilepsy patients taking non-inducing medications.
    MAJOR CONCLUSIONS: Carbamazepine use is associated with a reduction of 25OHD levels. In combination with other literature establishing the problematic metabolic effects of carbamazepine, this meta-analysis provides additional evidence in favor of the use of alternative ASMs as first-line agents. At minimum, vitamin D supplementation should be strongly considered for patients prescribed carbamazepine.
    Keywords:  25-hydroxycalciferol; 25-hydroxyvitamin D; Anti-seizure medications; Antiepileptic; Carbamazepine; Epilepsy; Hydoxyvitamin D; Meta-analysis; Osteopenia; Seizures; Vitamin D
    DOI:  https://doi.org/10.1016/j.eplepsyres.2021.106829
  46. J Ethnopharmacol. 2021 Nov 27. pii: S0378-8741(21)01100-4. [Epub ahead of print] 114870
    Systematic characterization of the metabolites of defatted walnut powder extract in vivo and screening of the mechanisms against NAFLD by UPLC-Q-Exactive Orbitrap MS combined with network pharmacology.
    Shu-Meng Ren, Qing-Zhu Zhang, Man Jiang, Meng-Lin Chen, Xia-Jing Xu, Dong-Mei Wang, Ying-Ni Pan, Xiao-Qiu Liu.
       ETHNOPHARMACOLOGICAL RELEVANCE: Walnut kernel, a well-known TCM, is often used after being defatted in tradition. And defatted walnut powder extract (DWPE) has the actions of tonifying the liver and kidney, dissipating stagnation and removing blood stasis, which has the effect on non-alcoholic fatty liver disease (NAFLD). However, the effective components of DWPE in vivo were unclear and the multiple mechanisms of DWPE against NAFLD have not been explored.
    AIM OF THE STUDY: The studies were performed to screen the effective substances in vivo by identification of the metabolites of DWPE in rats and to seek the potential mechanisms of DWPE on NAFLD by construction of the network pharmacology based on metabolites and verification of the highly correlated pathway.
    MATERIALS AND METHODS: To explore the effective substances in vivo, the metabolites of DWPE were identified in SD rats' bio-samples through UPLC-Q-Exactive Orbitrap MS. To analyze the mechanisms of DWPE on NAFLD, a Metabolite-Target-Disease network was established and the potential mechanisms were predicted. Then, highly correlated pathway was verified in animal and cells studies.
    RESULTS: A total of 52 metabolites of DWPE were identified in vivo, which were derived from gallic acid, ellagic acid (EA) and glansreginin A (Gla A). The possible metabolic pathways were phase Ⅰ (hydroxylation, hydrolyzation, etc) and phase Ⅱ metabolic reactions (methylation, sulfation and glucuronidation). Furthermore, in the network pharmacology, 54 core targets were enriched into pathways in cancer, nitrogen metabolism and other 9 pathways, which were essential pathways of DWPE against NAFLD. And the mechanism of nitrogen metabolism was verified in both of animal and cells studies. The results showed that DWPE could decline the concentration of ammonia and increase the expressions of carbonic anhydrase 2 (CA2) and carbamoylphosphate synthetase (CPS1) in nitrogen metabolism.
    CONCLUSION: Taken together, the study revealed the absorption components and their metabolic pathways and demonstrated the mechanism of nitrogen metabolism of DWPE on anti-NAFLD.
    Keywords:  Defatted walnut powder extract; Metabolic analysis in vivo; NAFLD; Network pharmacology; Nitrogen metabolism; UPLC-Q-exactive orbitrap MS
    DOI:  https://doi.org/10.1016/j.jep.2021.114870
  47. Cancer Cell Int. 2021 Nov 27. 21(1): 632
    To explore immune synergistic function of Quercetin in inhibiting breast cancer cells.
    Dan Qiu, Xianxin Yan, Xinqin Xiao, Guijuan Zhang, Yanqiu Wang, Jingyu Cao, Ruirui Ma, Shouyi Hong, Min Ma.
       BACKGROUND: The precancerous disease of breast cancer is an inevitable stage in the tumorigenesis and development of breast neoplasms. Quercetin (Que) has shown great potential in breast cancer treatment by inhibiting cell proliferation and regulating T cell function. γδ T cells are a class of nontraditional T cells that have long attracted attention due to their potential in immunotherapy. In this study, we revealed the immunomodulatory function of Que through regulation of the JAK/STAT1 signaling pathway, which was followed by the synergistic killing of breast cancer cells.
    METHODS: In the experimental design, we first screened target genes with or without Que treatment, and we intersected the Que target with the disease target by functional enrichment analysis. Second, MCF-10A, MCF-10AT, MCF-7 and MDA-MB-231 breast cancer cell lines were treated with Que for 0 h, 24 h and 48 h. Then, we observed the expression of its subsets by coculturing Que and γδ T cells and coculturing Que and γδ T cells with breast tumor cells to investigate their synergistic killing effect on tumor cells. Finally, Western blotting was used to reveal the changes in proteins related to the JAK/STAT1 signaling pathway after Que treatment in MCF-10AT and MCF-7 cells for 48 h.
    RESULTS: The pathway affected by Que treatment was the JAK/STAT1 signaling pathway and was associated with precancerous breast cancer, as shown by network pharmacology analysis. Que induced apoptosis of MCF-10AT, MCF-7 and MDA-MB-231 cells in a time- and concentration-dependent manner (P < 0.05). Most importantly, Que promoted the differentiation of γδ T cells into the Vδ2 T cell subpopulation. The best ratio of effector cells to target cells (E/T) was 10:1, the killing percentages of γδ T cells against MCF-10A, MCF-10AT, MCF-7, and MDA-MB-231 were 61.44 ± 4.70, 55.52 ± 3.10, 53.94 ± 2.74, and 53.28 ± 1.73 (P = 0.114, P = 0.486, and P = 0.343, respectively), and the strongest killing effect on precancerous breast cancer cells and breast cancer cells was found when the Que concentration was 5 μM and the E/T ratio was 10:1 (64.94 ± 3.61, 64.96 ± 5.45, 55.59 ± 5.98, and 59.04 ± 5.67, respectively). In addition, our results showed that Que increased the protein levels of IFNγ-R, p-JAK2 and p-STAT1 while decreasing the protein levels of PD-L1 (P < 0.0001).
    CONCLUSIONS: In conclusion, Que plays a synergistic role in killing breast cancer cells and promoting apoptosis by regulating the expression of IFNγ-R, p-JAK2, p-STAT1 and PD-L1 in the JAK/STAT1 signaling pathway and promoting the regulation of γδ T cells. Que may be a potential drug for the prevention of precancerous breast cancer and adjuvant treatment of breast cancer.
    Keywords:  Breast cancer; Breast precancerous lesion; JAK/STAT1 signaling pathway; Que; γδ T cell
    DOI:  https://doi.org/10.1186/s12935-021-02345-5
  48. PLoS Biol. 2021 Dec 03. 19(12): e3001468
    Cysteine and iron accelerate the formation of ribose-5-phosphate, providing insights into the evolutionary origins of the metabolic network structure.
    Gabriel Piedrafita, Sreejith J Varma, Cecilia Castro, Christoph Messner, Lukasz Szyrwiel, Julian L Griffin, Markus Ralser.
      The structure of the metabolic network is highly conserved, but we know little about its evolutionary origins. Key for explaining the early evolution of metabolism is solving a chicken-egg dilemma, which describes that enzymes are made from the very same molecules they produce. The recent discovery of several nonenzymatic reaction sequences that topologically resemble central metabolism has provided experimental support for a "metabolism first" theory, in which at least part of the extant metabolic network emerged on the basis of nonenzymatic reactions. But how could evolution kick-start on the basis of a metal catalyzed reaction sequence, and how could the structure of nonenzymatic reaction sequences be imprinted on the metabolic network to remain conserved for billions of years? We performed an in vitro screening where we add the simplest components of metabolic enzymes, proteinogenic amino acids, to a nonenzymatic, iron-driven reaction network that resembles glycolysis and the pentose phosphate pathway (PPP). We observe that the presence of the amino acids enhanced several of the nonenzymatic reactions. Particular attention was triggered by a reaction that resembles a rate-limiting step in the oxidative PPP. A prebiotically available, proteinogenic amino acid cysteine accelerated the formation of RNA nucleoside precursor ribose-5-phosphate from 6-phosphogluconate. We report that iron and cysteine interact and have additive effects on the reaction rate so that ribose-5-phosphate forms at high specificity under mild, metabolism typical temperature and environmental conditions. We speculate that accelerating effects of amino acids on rate-limiting nonenzymatic reactions could have facilitated a stepwise enzymatization of nonenzymatic reaction sequences, imprinting their structure on the evolving metabolic network.
    DOI:  https://doi.org/10.1371/journal.pbio.3001468
  49. Colloids Surf B Biointerfaces. 2021 Nov 20. pii: S0927-7765(21)00671-8. [Epub ahead of print]210 112225
    Two-step fabricating micelle-like nanoparticles of cisplatin with the 'real' long circulation and high bioavailability for cancer therapy.
    Hongbing Liu, Xiaowen Li, Muse Ji, Na Wang, Ying Xu, Yihan Kong, Jingxin Gou, Tian Yin, Haibing He, Yu Zhang, Xing Tang.
      Cisplatin is a widely used anticancer drug for various solid tumors. However, the serious adverse effects caused by systemic distribution limit its wide use. In this study, we intend to use biocompatible materials polyethyleneimine (PEI) and poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-PEG) to construct nanoparticles to enhance the efficacy of cisplatin and reduce its side effects. The micelle-like nanoparticles were fabricated by a simple two-step method, with a core consisting of PEI and cisplatin and a PLG-g-mPEG coating layer. The obtained nanoparticles have a small particle size (41.79 nm) and high drug loading (16.43%). The coated nanoparticles (NP-II) strengthened the structure of PEI and cisplatin complex (NP-I) and slowed the drug release for less than 20% at pH 7.4 PBS in 24 h. Therefore, it could effectively inhibit the binding of free drug and plasma proteins to achieve the long circulation, and the bioavailability could be increased to about 600% and 285% of cisplatin solution and NP-I respectively. Besides, the cellular uptake of NP-II was enhanced in the acidic tumor microenvironment due to the detachment of coating layer and the increase of positive zeta potential of nanoparticles, which was benefit to reduce the side effect of cisplatin to normal cells. In vivo pharmacodynamic experiments also showed that NP-II improved the efficacy and reduced side effects compared to the cisplatin solution. In conclusion, the two-step fabricating micelle-like nanoparticles with the improved therapeutic efficiency and reduced side effects show great potential for cancer chemotherapy.
    Keywords:  Cancer chemotherapy; Cisplatin; High bioavailability; Long circulation; Micelle-like nanoparticle
    DOI:  https://doi.org/10.1016/j.colsurfb.2021.112225
  50. Transl Oncol. 2021 Nov 30. pii: S1936-5233(21)00285-0. [Epub ahead of print]15(1): 101294
    Chlorogenic acid: Potential source of natural drugs for the therapeutics of fibrosis and cancer.
    Ebuka-Olisaemeka Nwafor, Peng Lu, Ying Zhang, Rui Liu, Hui Peng, Bin Xing, Yiting Liu, Ziwei Li, Kuibin Zhang, Yukun Zhang, Zhidong Liu.
      Fibrosis and cancer is described by some epidemiological studies as chronic stages of different disease conditions typically characterized by uncontrolled accumulation of extra-cellular matrix (ECM), thereby leading to inflammation of tissues and organ (lungs, heart, liver and kidney) dysfunction. It is highly prevalent, and contributes to increased mortality rate worldwide. Currently, the therapeutical approaches involving selected medications (bemcentinib, pirfenidone and nintedanib) obtained synthetically, and used in clinical practices for fibrosis and cancer management and treatment has shown to be unsatisfactorily, especially during progressive stages of the disease. With regards to finding a more potent, effective, and promising curative for fibrosis and cancer, there is need for continuous experimental studies universally. However, phytochemical constituents' particularly phenolic compounds [Chlorogenic acid (CGA)] obtained from coffee, and coffee beans have been predominantly utilized in experimental studies, due to its multiple pharmacological properties against various disease forms. Considering its natural source alongside minimal toxicity level, CGA, a major precursor of coffee have gained considerable attention nowadays from researchers worldwide, owing to its wide, efficacious and beneficial action against fibrosis and cancer. Interestingly, the safety of CGA has been proven. Furthermore, numerous experimental studies have also deduced massive remarkable outcomes in the use of CGA clinically, as a potential drug candidate against treatment of fibrosis and cancer. In the course of this review article, we systematically discussed the beneficial contributions of CGA with regards to its source, absorption, metabolism, mechanistic effects, and molecular mechanisms against different fibrosis and cancer categorization, which might be a prospective remedy in the future. Moreover, we also highlighted CGA (in vitro and in vivo analytical studies) defensive effects against various disorders.
    Keywords:  Cancer; Chlorogenic acid; Epithelial-mesenchymal transition; Fibrosis; Natural drugs
    DOI:  https://doi.org/10.1016/j.tranon.2021.101294
  51. Semin Cancer Biol. 2021 Nov 26. pii: S1044-579X(21)00281-9. [Epub ahead of print]
    Emerging trends in the application of gold nanoformulations in colon cancer diagnosis and treatment.
    Razan Aldahhan, Dana Almohazey, Firdos Alam Khan.
      Colorectal cancer is one of the most aggressive types of cancer with about two million new cases and one million deaths in 2020. The side effects of the available chemotherapies and the possibility of developing resistance against treatment highlight the importance of developing new therapeutic options. The development in the field of nanotechnology have introduced the application of nanoparticles (NPs) as a promising approach in the diagnosis and treatments of colorectal cancer and other types of cancer. Gold nanoparticles (AuNPs) are currently one of the most studied materials as they possess unique tunable properties allowing them to play a role in colorectal cancer bioimaging, diagnosis, and therapy. The high surface-to-volume ratio of AuNPs mediates their utilization in drug delivery as well as functionalization to provide specific targeting. Moreover, depending on their physical properties (size, shape), AuNPs can be modified to fit the intended application. However, there are contradictory results around the pharmacokinetics of AuNPs including their biodistribution, clearance, and toxicity. This variation of opinions is most likely due to the development of different AuNPs that vary in shape, size, and surface chemistry, in addition to the conditions under which each research was carried out. The conflicting data represent a challenge in the clinical use of AuNPs suggesting the need to understand the toxicity, fate, and long-term exposure of AuNPs in vivo. Thus, there is an unmet need for the establishment of a publicly available data base for extensive analysis. In this review, we discuss the recent advances in AuNP applications in the treatment and diagnosis of colorectal cancer, mechanisms of action, and clinical challenges.
    Keywords:  Anticancer agents; Colorectal cancer; Drug delivery; Gold nanoparticles
    DOI:  https://doi.org/10.1016/j.semcancer.2021.11.008
  52. Chin Med. 2021 Dec 02. 16(1): 129
    Traditional Chinese Medicine for adjuvant treatment of breast cancer: Taohong Siwu Decoction.
    Huajuan Jiang, Minmin Li, Kequn Du, Chuan Ma, Yanfen Cheng, Shengju Wang, Xin Nie, Chaomei Fu, Yao He.
      The high incidence of breast cancer is the greastest threat to women' health all over the world. Among them, HER-2 positive breast cancer has the characteristics of high malignancy, easy recurrence and metastasis, and poor prognosis. Traditional Chinese medicine (TCM) has a rich theoretical basis and clinical application for breast cancer. TCM believes that blood stasis syndrome is one of the important pathogenesis of breast formation and development. Taohong Siwu Decoction (TSHWD) is based on the "First Prescription of Gynecology" Siwu Decoction. It is widely used in various blood stasis and blood deficiency syndromes, mainly in gynecological blood stasis. Clinical studies have found that THSWD can treat breast cancer by reducing blood vessel and lymphangiogenesis with auxiliary chemotherapy. In this study, we aim to explore the material basis and mechanism of THSWD in the treatment of HER-2 positive breast cancer through literature review and network pharmacology studies. Through a literature review of the traditional application, chemical composition of Chinese herbal medicine of THSWD, as well as its clinical reports and pharmacological research on breast cancer treatment. Meanwhile, we conducted "component-pathway-target" network through network pharmacology reveals the main material basis, possible targets and pathways of THSWD in inhibiting HER-2 positive breast cancer. Literature review and network pharmacology research results had predicted that, baicalein, kaempferol, caffeic acid, amygdalin, quercetin, ferulic acid, gallic acid, catalpol, hydroxysafflor yellow A, paeoniflorin in THSWD are the main effective chemical composition. THSWD regulates 386 protein targets and 166 pathways related to breast cancer. The molecular mechanism is mainly to improve the microenvironment of tumor cells, regulate the process of tumor cell EMT, and inhibit tumor cell proliferation and metastasis. This study revealed the mechanism of action of THSWD in the treatment of HER-2 positive breast cancer through literature review and network pharmacology studies, providing a scientific basis for clinical application.
    DOI:  https://doi.org/10.1186/s13020-021-00539-7
  53. Front Bioeng Biotechnol. 2021 ;9 773021
    Tumor Cell Distinguishable Nanomedicine Integrating Chemotherapeutic Sensitization and Protection.
    Sen Liu, Can Shen, Cheng Qian, Jianquan Wang, Zhongmei Yang, Yanchun Wei, Li Quan, Changjiang Pan, Yong Hu, Wei Ye.
      Theoretically, with a high enough drug dosage, cancer cells could be eliminated. However, the dosages that can be administered are limited by the therapeutic efficacy and side effects of the given drug. Herein, a nanomedicine integrating chemotherapeutic sensitization and protection was developed to relieve the limitation of administration dosage and to improve the efficacy of chemotherapy. The nanomedicine was endowed with the function of synergistically controlled release of CO and drugs under near-infrared (NIR) light irradiation. CO photo-induced release system (COPIRS) was synthesized by constructing an electron excitation-electron transfer group-electron-induced CO release structure and was used as the hydrophobic part, and then hydrophilic polymer (polyethylene glycol; PEG) was introduced by a thermal-responsive groups (DA group), forming a near-infrared-induced burst-release nanocarrier. In vitro and in vivo experiments showed that the nanomedicine can distinguish between tumor and normal cells and regulates the resistance of these different cells through the controlled release of carbonic oxide (CO), simultaneously enhancing the efficacy of chemotherapy drugs on tumor cells and chemotherapeutic protection on normal cells. This strategy could solve the current limitations on dosages due to toxicity and provide a solution for tumor cure by chemotherapy.
    Keywords:  NIR-controlled release; cell distinguishing; chemotherapeutic protection; chemotherapeutic sensitization; chemotherapy
    DOI:  https://doi.org/10.3389/fbioe.2021.773021
  54. World Neurosurg. 2021 Nov 30. pii: S1878-8750(21)01814-3. [Epub ahead of print]
    Clinical Trials in Spinal Tumors: A Two-Decade Review.
    Emily K Chapman, Aly A Valliani, William H Shuman, Michael L Martini, Sean N Neifert, Jeffrey T Gilligan, Frank J Yuk, Alexander J Schupper, Jonathan S Gal, John M Caridi.
       OBJECTIVE: Clinical trials are essential for assessing advancements in spine tumor therapeutics. The purpose of this study is to characterize trends in clinical trials for primary and metastatic tumor treatments over the past two decades.
    METHODS: ClinicalTrials.gov was queried using the search term "spine" for all interventional studies spanning 1999 to 2020 with categories of "Cancer", "Neoplasm", "Tumor", or "Metastasis". Tumor type, phase data, enrollment numbers and home institution country were recorded. The sponsor was categorized as academic institution, industry, government or other and intervention type as procedure, drug, device, radiation or other. Frequency of each category and cumulative frequency over twenty years were calculated.
    RESULTS: 106 registered trials for spine tumors were listed. All except two that began before 2008 have been completed, enrollment of 51-100 subjects (29.8%) was the most common, and the majority were phase II (54.4%). Most examined metastatic tumors (58.5%) and new trials per year increased 3.4-fold between 2009 and 2020. The majority were conducted in the United States (56.4%). The most common intervention strategy was radiation (32.1%), although between 2010-2020 procedural studies became the most frequent (2.4 per year). The majority were sponsored by academic institutions (63.2%), and over twenty years have sponsored 3.2-fold more studies than industry partners.
    CONCLUSIONS: The number of clinical trials for spine tumor therapies has rapidly increased over the past 15 years, driven by studies at United States academic medical institutions investigating radiosurgery for treatment of metastases. Targeted therapies for tumor subtypes and sequelae have updated international best practices.
    Keywords:  clinical trial; metastasis; radiosurgery; spine; tumor
    DOI:  https://doi.org/10.1016/j.wneu.2021.11.101
  55. Breast Cancer Res Treat. 2021 Nov 30.
    Breast cancer vaccines for treatment and prevention.
    Mary L Disis, Denise L Cecil.
      Breast cancer is immunogenic and a variety of vaccines have been designed to boost immunity directed against the disease. The components of a breast cancer vaccine, the antigen, the delivery system, and the adjuvant, can have a significant impact on vaccine immunogenicity. There have been numerous immunogenic proteins identified in all subtypes of breast cancer. The majority of these antigens are weakly immunogenic nonmutated tumor-associated proteins. Mutated proteins and neoantigen epitopes are found only in a small minority of patients and are enriched in the triple negative subtype. Several vaccines have advanced to large randomized Phase II or Phase III clinical trials. None of these trials met their primary endpoint of either progression-free or overall survival. Despite these set-backs investigators have learned important lessons regarding the clinical application of breast cancer vaccines from the type of immune response needed for tumor eradication, Type I T-cell immunity, to the patient populations most likely to benefit from vaccination. Many therapeutic breast cancer vaccines are now being tested in combination with other forms of immune therapy or chemotherapy and radiation. Breast cancer vaccines as single agents are now studied in the context of the prevention of relapse or development of disease. Newer approaches are designing vaccines to prevent breast cancer by intercepting high-risk lesions such as ductal carcinoma in situ to limit the progression of these tumors to invasive cancer. There are also several efforts to develop vaccines for the primary prevention of breast cancer by targeting antigens expressed during breast cancer initiation.
    Keywords:  Antigen; Clinical trials; Prevention; T-cell; Treatment; Vaccine
    DOI:  https://doi.org/10.1007/s10549-021-06459-2
  56. Bioelectrochemistry. 2021 Nov 17. pii: S1567-5394(21)00264-4. [Epub ahead of print]144 108001
    High-frequency irreversible electroporation brain tumor ablation: exploring the dynamics of cell death and recovery.
    Kelsey R Murphy, Kenneth N Aycock, Alayna N Hay, John H Rossmeisl, Rafael V Davalos, Nikolaos G Dervisis.
      Improved therapeutics for malignant brain tumors are urgently needed. High-frequency irreversible electroporation (H-FIRE) is a minimally invasive, nonthermal tissue ablation technique, which utilizes high-frequency, bipolar electric pulses to precisely kill tumor cells. The mechanisms of H-FIRE-induced tumor cell death and potential for cellular recovery are incompletely characterized. We hypothesized that tumor cells treated with specific H-FIRE electric field doses can survive and retain proliferative capacity. F98 glioma and LL/2 Lewis lung carcinoma cell suspensions were treated with H-FIRE to model primary and metastatic brain cancer, respectively. Cell membrane permeability, apoptosis, metabolic viability, and proliferative capacity were temporally measured using exclusion dyes, condensed chromatin staining, WST-8 fluorescence, and clonogenic assays, respectively. Both tumor cell lines exhibited dose-dependent permeabilization, with 1,500 V/cm permitting and 3,000 V/cm inhibiting membrane recovery 24 h post-treatment. Cells treated with 1,500 V/cm demonstrated significant and progressive recovery of apoptosis and metabolic activity, in contrast to cells treated with higher H-FIRE doses. Cancer cells treated with recovery-permitting doses of H-FIRE maintained while those treated with recovery-inhibiting doses lost proliferative capacity. Taken together, our data suggest that H-FIRE induces reversible and irreversible cellular damage in a dose-dependent manner, and the presence of dose-dependent recovery mechanisms permits tumor cell proliferation.
    Keywords:  Apoptosis; Brain cancer; Cell death; High-frequency irreversible electroporation; Proliferation; Recovery
    DOI:  https://doi.org/10.1016/j.bioelechem.2021.108001
  57. Eur J Pharm Biopharm. 2021 Nov 28. pii: S0939-6411(21)00337-4. [Epub ahead of print]
    Nanocarriers targeting the diseases of the pancreas.
    Nurbanu Demirtürk, Erem Bilensoy.
      Diseases of the pancreas include acute and chronic pancreatitis, exocrine pancreatic insufficiency, diabetes and pancreatic cancer. These pathologies can be difficult to treat due to the innate properties of the pancreas, its structure and localization. The need for effective targeting of the pancreatic tissue by means of nanoparticles delivering therapeutics is a major focus area covered and discussed in this review. Most common diseases of the pancreas do not have specific and direct medical treatment option, and existing treatment options are generally aimed at relieving symptoms. Diabetes has different treatment options for different subtypes based on insulin having stability problems and requiring injections reducing patient compliance. Pancreatic cancer progresses silently and can only be diagnosed in advanced stages. Therefore, survival rate of patients is very low. Gemcitabine and FOLFIRINOX treatment regimens, the most commonly used clinical standard treatments, are generally insufficient due to the chemoresistance that develops in cancer cells and also various side effects. Therefore new treatment options for pancreatic cancer are also under focus. Overcoming drug resistance and pancreatic targeting can be achieved with active and passive targeting methods, and a more effective and safer treatment regimen can be provided at lower drug doses. This review covers the current literature and clinical trials concerning pancreatic drug delivery systems in the nanoscale focusing on the challenges and opportunities provided by these smart delivery systems.
    Keywords:  diabetes; drug delivery system; exocrine pancreatic insufficiency; nanoparticle; pancreas; pancreatic cancer; pancreatitis
    DOI:  https://doi.org/10.1016/j.ejpb.2021.11.006
  58. Recent Pat Anticancer Drug Discov. 2021 Nov 30.
    Pharmacological potentials and Nutritional values of Tropical and Sub-tropical Fruits of India: Emphasis on their anticancer bioactive components.
    Arunaksharan Narayanankutty.
       BACKGROUND: Fruits are an important dietary component, which supply vitamins, minerals, as well as dietary fiber. In addition, they are rich sources of various biological and pharmacologically active compounds. Among these, temperate fruits are well studied for their pharmacological potentials, whereas tropical/subtropical fruits are less explored for their health impacts. In India, most of the consumed fruits are either tropical or subtropical.
    OBJECTIVES: The present review aims to provide a health impact of major tropical and sub-tropical fruits of India, emphasizing their anticancer efficacy. In addition, the identified bioactive components from these fruits exhibiting anticancer efficacy are also discussed along with the patent literature published.
    METHODS: The literature was collected from various repositories, including NCBI, ScienceDirect, Eurekaselect, and Web of Science; literature from predatory journals was omitted during the process. Patent literature was collected from google patents and similar patent databases.
    RESULTS: Tropical fruits are rich sources of various nutrients and bioactive components including polyphenols, flavonoids, anthocyanin, etc. By virtue of these biomolecules, tropical fruits have been shown to interfere with various steps in carcinogenesis, metastasis, and drug resistance. Their mode of action is either by activation of apoptosis, regulation of cell cycle, inhibition of cell survival and proliferation pathways, increased lipid trafficking or inhibiting inflammatory pathways. Several molecules and combinations have been patented for their anticancer and chemoprotective properties.
    CONCLUSION: Overall, the present concludes that Indian tropical/ subtropical fruits are nutritionally and pharmacologically active and may serve as a source of novel anticancer agents in the future.
    Keywords:  Anti-inflammatory activity; Antioxidant activity; Bioactive compounds; Indian tropical fruits; cancer; degenerative diseases
    DOI:  https://doi.org/10.2174/1574892816666211130165200
  59. Pharmacol Res. 2021 Nov 26. pii: S1043-6618(21)00589-2. [Epub ahead of print] 106005
    Old wine in new bottles: kaempferol is a promising agent for treating the trilogy of liver diseases.
    Xiaolin Xiao, Qichao Hu, Xinyu Deng, Kaiyun Shi, Wenwen Zhang, Yinxiao Jiang, Xiao Ma, Jinhao Zeng.
      As a source of various compounds, natural products have long been important and valuable for drug development. Kaempferol (KP) is the most common flavonol with bioactive activity and has been extracted from many edible plants and traditional Chinese medicines. It has a wide range of pharmacological effects on inflammation, oxidation, and tumour and virus regulation. The liver is an important organ and is involved in metabolism and activity. Because the pathological process of liver diseases is extremely complicated, liver diseases involving ALD, NASH, liver fibrosis, and HCC are often complicated and difficult to treat. Fortunately, there have been many reports that KP has a good pharmacological effect on a series of complex liver diseases. To fully understand the mechanism of KP and provide new ideas for its clinical application in the treatment of liver diseases, this article reviews the pharmacological mechanism and potential value of KP in different studies involving various liver diseases. In the trilogy of liver disease, high concentrations of ROS stimulate peroxidation and activate the inflammatory signal cascade, which involves signalling pathways such as MAPK/JAK-STAT/PERK/Wnt/Hipp, leading to varying degrees of cell degradation and liver damage. The development of liver disease is promoted in an inflammatory environment, which is conducive to the activation of TGF-β1, leading to increased expression of pro-fibrosis and pro-inflammatory genes. Inflammation and oxidative stress promote the formation of tumour microenvironments, and uncontrolled autophagy of cancer cells further leads to the development of liver cancer. The main pathway in this process is AMPK/PTEN/PI3K-Akt/TOR. KP can not only protect liver parenchymal cells through a variety of antioxidant and anti-apoptotic mechanisms but also reduces the immune inflammatory response in the liver microenvironment, thereby preventing cell apoptosis; it can also inhibit the ER stress response, prevent inflammation and inhibit tumour growth. KP exerts multiple therapeutic effects on liver disease by regulating precise signalling targets and is expected to become an emerging therapeutic opportunity to treat liver disease in the future.
    Keywords:  ER stress; Kaempferol; alcoholic liver disease; hepatic fibrosis; hepatocellular carcinomas; non-alcoholic steatohepatitis
    DOI:  https://doi.org/10.1016/j.phrs.2021.106005
  60. Bioengineered. 2021 Dec 02.
    New Challenges in the Use of Nanomedicine in Cancer Therapy.
    Mahmood Rasool, Arif Malik, Sulayman Waquar, Mahwish Arooj, Sara Zahid, Muhammad Asif, Sumaira Shaheen, Abrar Hussain, Hamid Ullah, Siew Hua Gan.
      Nanomedicines are applied as alternative treatments for anticancer agents. For the treatment of cancer, due to the small size in nanometers (nm), specific site targeting can be achieved with the use of nanomedicines, increasing their bioavailability and conferring fewer toxic side effects. Additionally, the use of minute amounts of drugs can lead to cost savings. In addition, nanotechnology is effectively applied in the preparation of such drugs as they are in nm sizes, considered one of the earliest cutoff values for the production of products utilized in nanotechnology. Early concepts described gold nanoshells as one of the successful therapies for cancer and associated diseases where the benefits of nanomedicine include effective active or passive targeting. Common medicines are degraded at a higher rate, whereas the degradation of macromolecules is time-consuming. All of the discussed properties are responsible for executing the physiological behaviors occurring at the following scale, depending on the geometry. Finally, large nanomaterials based on organic, lipid, inorganic, protein, and synthetic polymers have also been utilized to develop novel cancer cures.
    Keywords:  Active targeting; Nanomaterials; Nanomedicine; Nanoshells; Passive targeting
    DOI:  https://doi.org/10.1080/21655979.2021.2012907
  61. Sci Rep. 2021 Dec 01. 11(1): 23264
    Pan-cancer analysis of non-oncogene addiction to DNA repair.
    Luis Bermúdez-Guzmán.
      Cancer cells usually depend on the aberrant function of one or few driver genes to initiate and promote their malignancy, an attribute known as oncogene addiction. However, cancer cells might become dependent on the normal cellular functions of certain genes that are not oncogenes but ensure cell survival (non-oncogene addiction). The downregulation or silencing of DNA repair genes and the consequent genetic and epigenetic instability is key to promote malignancy, but the activation of the DNA-damage response (DDR) has been shown to become a type of non-oncogene addiction that critically supports tumour survival. In the present study, a systematic evaluation of DNA repair addiction at the pan-cancer level was performed using data derived from The Cancer Dependency Map and The Cancer Genome Atlas (TCGA). From 241 DDR genes, 59 were identified as commonly essential in cancer cell lines. However, large differences were observed in terms of dependency scores in 423 cell lines and transcriptomic alterations across 18 cancer types. Among these 59 commonly essential genes, 14 genes were exclusively associated with better overall patient survival and 19 with worse overall survival. Notably, a specific molecular signature among the latter, characterized by DDR genes like UBE2T, RFC4, POLQ, BRIP1, and H2AFX showing the weakest dependency scores, but significant upregulation was strongly associated with worse survival. The present study supports the existence and importance of non-oncogenic addiction to DNA repair in cancer and may facilitate the identification of prognostic biomarkers and therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s41598-021-02773-3
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