bims-kracam 2021-09-12 papers

on K-Ras in cancer metabolism

Issue of 2021–09–12
forty papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development

MYC Rules: Leading Glutamine Metabolism toward a Distinct Cancer Cell Phenotype.
Lipid Metabolism Regulates Oxidative Stress and Ferroptosis in RAS-Driven Cancers: A Perspective on Cancer Progression and Therapy.
More Than Meets the Eye Regarding Cancer Metabolism.
Genomic instability and metabolism in cancer.
The nexus between redox state and intermediary metabolism.
The potentials of carbon monoxide-releasing molecules in cancer treatment: An outlook from ROS biology and medicine.
Targeting KRAS in pancreatic cancer: new drugs on the horizon.
Future perspective: metabolism as a therapeutic target in acute myeloid leukemia - from Warburg to precision medicine.
Application of glutathione depletion in cancer therapy: Enhanced ROS-based therapy, ferroptosis, and chemotherapy.
CircMYH9 drives colorectal cancer growth by regulating serine metabolism and redox homeostasis in a p53-dependent manner.
Cross-Talk between Oxidative Stress and m6A RNA Methylation in Cancer.
The role of glycometabolic plasticity in cancer.
Notch1/TAZ axis promotes aerobic glycolysis and immune escape in lung cancer.
Targeting Amino Acid Metabolic Reprogramming via L-Type Amino Acid Transporter 1 (LAT1) for Endocrine-Resistant Breast Cancer.
Current understanding of ferroptosis in the progression and treatment of pancreatic cancer.
Glutamine promotes escape from therapy-induced senescence in tumor cells.
Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation.
The Role of Oncogenes and Redox Signaling in the Regulation of PD-L1 in Cancer.
Anti-tumor effects of vitamin D in glioblastoma: mechanism and therapeutic implications.
A Comprehensive Review of the Use of Antioxidants and Natural Products in Cancer Patients Receiving Anticancer Therapy.
The metabolic flexibility of quiescent CSC: implications for chemotherapy resistance.
RAS specific protease induces irreversible growth arrest via p27 in several KRAS mutant colorectal cancer cell lines.
α-Mangostin Nanoparticles Cytotoxicity and Cell Death Modalities in Breast Cancer Cell Lines.
Role of glutamine and its metabolite ammonia in crosstalk of cancer-associated fibroblasts and cancer cells.
Effects of PI3K inhibition in AI-resistant breast cancer cell lines: autophagy, apoptosis, and cell cycle progression.
T cells critically depend on pyruvate oxidation.
Piperlongumine, a Potent Anticancer Phytotherapeutic, Induces Cell Cycle Arrest and Apoptosis In Vitro and In Vivo through the ROS/Akt Pathway in Human Thyroid Cancer Cells.
Curcumin as an Adjuvant to Cancer Immunotherapy.
Stress-activated kinases as therapeutic targets in pancreatic cancer.
A Perspective on Withania somnifera Modulating Antitumor Immunity in Targeting Prostate Cancer.
Impacting the Remedial Potential of Nano Delivery-Based Flavonoids for Breast Cancer Treatment.
Ellagic acid-loaded, tween 80-coated, chitosan nanoparticles as a promising therapeutic approach against breast cancer: In-vitro and in-vivo study.
Metabolic rewiring is associated with HPV-specific profiles in cervical cancer cell lines.
Additive effects of resveratrol and doxorubicin on bladder cancer cells.
Pharmacokinetic and Pharmacodynamic Assessment of Hydroxychloroquine in Breast Cancer.
Current clinical developments in curcumin-based therapeutics for cancer and chronic diseases.
Liquiritigenin exerts the anti-cancer role in oral cancer via inducing autophagy-related apoptosis through PI3K/AKT/mTOR pathway inhibition in vitro and in vivo.
Ultrasound responsive self-assembled micelles loaded with hypocrellin for cancer sonodynamic therapy.
Chemo-Preventive Action of Resveratrol: Suppression of p53-A Molecular Targeting Approach.
Novel insights into the pathogenesis and treatment of NRAS mutant melanoma.

Cancers (Basel). 2021 Sep 06. pii: 4484. [Epub ahead of print]13(17):

MYC Rules: Leading Glutamine Metabolism toward a Distinct Cancer Cell Phenotype.

Vincent Tambay, Valérie-Ann Raymond, Marc Bilodeau.

  Metabolic reprogramming and deregulated cellular energetics are hallmarks of cancer. The aberrant metabolism of cancer cells is thought to be the product of differential oncogene activation and tumor suppressor gene inactivation. MYC is one of the most important oncogenic drivers, its activation being reported in a variety of cancer types and sub-types, among which are the most prevalent and aggressive of all malignancies. This review aims to offer a comprehensive overview and highlight the importance of the c-Myc transcription factor on the regulation of metabolic pathways, in particular that of glutamine and glutaminolysis. Glutamine can be extensively metabolized into a variety of substrates and be integrated in a complex metabolic network inside the cell, from energy metabolism to nucleotide and non-essential amino acid synthesis. Together, understanding metabolic reprogramming and its underlying genetic makeup, such as MYC activation, allows for a better understanding of the cancer cell phenotype and thus of the potential vulnerabilities of cancers from a metabolic standpoint.

Keywords:  MYC; glutamine metabolism; oncogene

DOI:  https://doi.org/10.3390/cancers13174484
Front Mol Biosci. 2021 ;8 706650

Lipid Metabolism Regulates Oxidative Stress and Ferroptosis in RAS-Driven Cancers: A Perspective on Cancer Progression and Therapy.

Caterina Bartolacci, Cristina Andreani, Yasmin El-Gammal, Pier Paolo Scaglioni.

  HRAS, NRAS and KRAS, collectively referred to as oncogenic RAS, are the most frequently mutated driver proto-oncogenes in cancer. Oncogenic RAS aberrantly rewires metabolic pathways promoting the generation of intracellular reactive oxygen species (ROS). In particular, lipids have gained increasing attention serving critical biological roles as building blocks for cellular membranes, moieties for post-translational protein modifications, signaling molecules and substrates for ß-oxidation. However, thus far, the understanding of lipid metabolism in cancer has been hampered by the lack of sensitive analytical platforms able to identify and quantify such complex molecules and to assess their metabolic flux in vitro and, even more so, in primary tumors. Similarly, the role of ROS in RAS-driven cancer cells has remained elusive. On the one hand, ROS are beneficial to the development and progression of precancerous lesions, by upregulating survival and growth factor signaling, on the other, they promote accumulation of oxidative by-products that decrease the threshold of cancer cells to undergo ferroptosis. Here, we overview the recent advances in the study of the relation between RAS and lipid metabolism, in the context of different cancer types. In particular, we will focus our attention on how lipids and oxidative stress can either promote or sensitize to ferroptosis RAS driven cancers. Finally, we will explore whether this fine balance could be modulated for therapeutic gain.

Keywords:  RAS oncogenes; ferroptosis; lipid metabolism; oxidative stress; tumorigenesis

DOI:  https://doi.org/10.3389/fmolb.2021.706650
Int J Mol Sci. 2021 Sep 01. pii: 9507. [Epub ahead of print]22(17):

More Than Meets the Eye Regarding Cancer Metabolism.

Anna Kubicka, Karolina Matczak, Magdalena Łabieniec-Watała.

  In spite of the continuous improvement in our knowledge of the nature of cancer, the causes of its formation and the development of new treatment methods, our knowledge is still incomplete. A key issue is the difference in metabolism between normal and cancer cells. The features that distinguish cancer cells from normal cells are the increased proliferation and abnormal differentiation and maturation of these cells, which are due to regulatory changes in the emerging tumour. Normal cells use oxidative phosphorylation (OXPHOS) in the mitochondrion as a major source of energy during division. During OXPHOS, there are 36 ATP molecules produced from one molecule of glucose, in contrast to glycolysis which provides an ATP supply of only two molecules. Although aerobic glucose metabolism is more efficient, metabolism based on intensive glycolysis provides intermediate metabolites necessary for the synthesis of nucleic acids, proteins and lipids, which are in constant high demand due to the intense cell division in cancer. This is the main reason why the cancer cell does not "give up" on glycolysis despite the high demand for energy in the form of ATP. One of the evolving trends in the development of anti-cancer therapies is to exploit differences in the metabolism of normal cells and cancer cells. Currently constructed therapies, based on cell metabolism, focus on the attempt to reprogram the metabolic pathways of the cell in such a manner that it becomes possible to stop unrestrained proliferation.

Keywords:  Warburg effect; cancer metabolism; glutamine; glycolysis; lactate; tumour heterogeneity

DOI:  https://doi.org/10.3390/ijms22179507
Int Rev Cell Mol Biol. 2021 ;pii: S1937-6448(21)00063-0. [Epub ahead of print]364 241-265

Genomic instability and metabolism in cancer.

Haojian Li, Susan E Zimmerman, Urbain Weyemi.

  Genomic instability and metabolic reprogramming are among the key hallmarks discriminating cancer cells from normal cells. The two phenomena contribute to the robust and evasive nature of cancer, particularly when cancer cells are exposed to chemotherapeutic agents. Genomic instability is defined as the increased frequency of mutations within the genome, while metabolic reprogramming is the alteration of metabolic pathways that cancer cells undergo to adapt to increased bioenergetic demand. An underlying source of these mutations is the aggregate product of damage to the DNA, and a defective repair pathway, both resulting in the expansion of genomic lesions prior to uncontrolled proliferation and survival of cancer cells. Exploitation of DNA damage and the subsequent DNA damage response (DDR) have aided in defining therapeutic approaches in cancer. Studies have demonstrated that targeting metabolic reprograming yields increased sensitivity to chemo- and radiotherapies. In the past decade, it has been shown that these two key features are interrelated. Metabolism impacts DNA damage and DDR via regulation of metabolite pools. Conversely, DDR affects the response of metabolic pathways to therapeutic agents. Because of the interplay between genomic instability and metabolic reprogramming, we have compiled findings which more selectively highlight the dialog between metabolism and DDR, with a particular focus on glucose metabolism and double-strand break (DSB) repair pathways. Decoding this dialog will provide significant clues for developing combination cancer therapies.

Keywords:  Cancer; DNA repair; Genomic instability; Glycolysis; Metabolism; Mitochondrial homeostasis

DOI:  https://doi.org/10.1016/bs.ircmb.2021.05.004
FEBS J. 2021 Sep 08.

The nexus between redox state and intermediary metabolism.

Anna Zoccarato, Adam A Nabeebaccus, Rafael R Oexner, Celio Xc Santos, Ajay M Shah.

  Reactive oxygen species (ROS) are not just a by-product of cellular metabolic processes but act as signalling molecules that regulate both physiological and pathophysiological processes. A close connection exists in cells between redox homeostasis and cellular metabolism. In this review, we describe how intracellular redox state and glycolytic intermediary metabolism are closely coupled. On the one hand, ROS signalling can control glycolytic intermediary metabolism by direct regulation of the activity of key metabolic enzymes and indirect regulation via redox-sensitive transcription factors. On the other hand, metabolic adaptation and reprogramming in response to physiological or pathological stimuli regulate intracellular redox balance, through mechanisms such as the generation of reducing equivalents. We also discuss the impact of these intermediary metabolism-redox circuits in physiological and disease settings across different tissues. A better understanding of the mechanisms regulating these intermediary metabolism-redox circuits will be crucial to the development of novel therapeutic strategies.

Keywords:  Intermediary metabolism; Redox; Warburg effect; anabolism; reactive oxygen species

DOI:  https://doi.org/10.1111/febs.16191
Redox Biol. 2021 Sep 06. pii: S2213-2317(21)00283-4. [Epub ahead of print]46 102124

The potentials of carbon monoxide-releasing molecules in cancer treatment: An outlook from ROS biology and medicine.

Thi Thuy Tien Vo, Quang Canh Vo, Vo Phuoc Tuan, Yinshen Wee, Hsin-Chung Cheng, I-Ta Lee.

  Carbon monoxide (CO) is now well recognized a pivotal endogenous signaling molecule in mammalian lives. The proof-of-concept employing chemical carriers of exogenous CO as prodrugs for CO release, also known as CO-releasing molecules (CO-RMs), has been appreciated. The major advantage of CO-RMs is that they are able to deliver CO to the target sites in a controlled manner. There is an increasing body of experimental studies suggesting the therapeutic potentials of CO and CO-RMs in different cancer models. This review firstly presents a short but crucial view concerning the characteristics of CO and CO-RMs. Then, the anticancer activities of CO-RMs that target many cancer hallmarks, mainly proliferation, apoptosis, angiogenesis, and invasion and metastasis, are discussed. However, their anticancer activities are varying and cell-type specific. The aerobic metabolism of molecular oxygen inevitably generates various oxygen-containing reactive metabolites termed reactive oxygen species (ROS) which play important roles in both physiology and pathophysiology. Although ROS act as a double-edged sword in cancer, both sides of which may potentially have been exploited for therapeutic benefits. The main focus of the present review is thus to identify the possible signaling network by which CO-RMs can exert their anticancer actions, where ROS play the central role. Another important issue concerning the potential effect of CO-RMs on the aerobic glycolysis (the Warburg effect) which is a feature of cancer metabolic reprogramming is given before the conclusion with future prospects on the challenges of developing CO-RMs into clinically pharmaceutical candidates in cancer therapy.

Keywords:  Apoptosis; Carbon monoxide; Carbon monoxide-releasing molecules; Pro-tumorigenic pathways; Reactive oxygen species; Warburg effect

DOI:  https://doi.org/10.1016/j.redox.2021.102124
Cancer Metastasis Rev. 2021 Sep 09.

Targeting KRAS in pancreatic cancer: new drugs on the horizon.

Sahar F Bannoura, Md Hafiz Uddin, Misako Nagasaka, Farzeen Fazili, Mohammed Najeeb Al-Hallak, Philip A Philip, Bassel El-Rayes, Asfar S Azmi.

  Kirsten Rat Sarcoma (KRAS) is a master oncogene involved in cellular proliferation and survival and is the most commonly mutated oncogene in all cancers. Activating KRAS mutations are present in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases and are implicated in tumor initiation and progression. Although KRAS is a critical oncogene, and therefore an important therapeutic target, its therapeutic inhibition has been very challenging, and only recently specific mutant KRAS inhibitors have been discovered. In this review, we discuss the activation of KRAS signaling and the role of mutant KRAS in PDAC development. KRAS has long been considered undruggable, and many drug discovery efforts which focused on indirect targeting have been unsuccessful. We discuss the various efforts for therapeutic targeting of KRAS. Further, we explore the reasons behind these obstacles, novel successful approaches to target mutant KRAS including G12C mutation as well as the mechanisms of resistance.

Keywords:  KRAS; KRAS inhibitor; KRAS vaccine; KRASG12C; KRASG12C inhibitors; PROTACs; Pancreatic cancer

DOI:  https://doi.org/10.1007/s10555-021-09990-2
Curr Med Res Opin. 2021 Sep 09. 1

Future perspective: metabolism as a therapeutic target in acute myeloid leukemia - from Warburg to precision medicine.

Kimberley Joanne Hatfield, Ida Sofie Grønningsaeter, Håkon Reikvam.

  Acute myeloid leukemia (AML) is a highly malignant blood cancer disease, with dismal prognosis. The theory that cancer cells utilize metabolism to their growth advantage was postulated almost hundred years ago. However, only recently have been able to take advantage of this Achilles heel of malignant cell growth. Current observations suggest a crucial role for various metabolic pathways in AML, and special in leukemia stem cells (LSC), believed to be responsible for re-initiation of the leukemic clone, and hence relapse of this devastating disease. In the present article we discuss the features for metabolism in AML based on recent research, and special emphasizing the potential of pharmacological inhibiting metabolism as new treatment approaches.

Keywords:  Acute myelogenous leukemia – Leukemia stem cells – Metabolism – Signaling pathways – Targeted therapy

DOI:  https://doi.org/10.1080/03007995.2021.1978960
Biomaterials. 2021 Aug 30. pii: S0142-9612(21)00466-X. [Epub ahead of print]277 121110

Application of glutathione depletion in cancer therapy: Enhanced ROS-based therapy, ferroptosis, and chemotherapy.

Boyi Niu, Kaixin Liao, Yixian Zhou, Ting Wen, Guilan Quan, Xin Pan, Chuanbin Wu.

  Glutathione (GSH) is an important member of cellular antioxidative system. In cancer cells, a high level of GSH is indispensable to scavenge excessive reactive oxygen species (ROS) and detoxify xenobiotics, which make it a potential target for cancer therapy. Plenty of studies have shown that loss of intracellular GSH makes cancer cells more susceptible to oxidative stress and chemotherapeutic agents. GSH depletion has been proved to improve the therapeutic efficacy of ROS-based therapy (photodynamic therapy, sonodynamic therapy, and chemodynamic therapy), ferroptosis, and chemotherapy. In this review, various strategies for GSH depletion used in cancer therapy are comprehensively summarized and discussed. First, the functions of GSH in cancer cells are analyzed to elucidate the necessity of GSH depletion in cancer therapy. Then, the synthesis and metabolism of GSH are briefly introduced to bring up some crucial targets for GSH modulation. Finally, different approaches to GSH depletion in the literature are classified and discussed in detail according to their mechanisms. Particularly, functional materials with GSH-consuming ability based on nanotechnology are elaborated due to their unique advantages and potentials. This review presents the ingenious application of GSH-depleting strategy in cancer therapy for improving the outcomes of various therapeutic regimens, which may provide useful guidance for designing intelligent drug delivery system.

Keywords:  Cancer therapy; Drug resistance; Ferroptosis; Glutathione depletion; Nanomaterials; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.biomaterials.2021.121110
Mol Cancer. 2021 Sep 08. 20(1): 114

CircMYH9 drives colorectal cancer growth by regulating serine metabolism and redox homeostasis in a p53-dependent manner.

Xin Liu, Yunze Liu, Zhao Liu, Changwei Lin, Fanchao Meng, Lei Xu, Xiuzhong Zhang, Chong Zhang, Penbo Zhang, Shuai Gong, Nai Wu, Zeqiang Ren, Jun Song, Yi Zhang.

   BACKGROUND: Circular RNAs (circRNAs) play important roles in cancer progression and metabolism regulation. Serine/glycine metabolism supports the growth of cancer cells by contributing to their anabolic demands and epigenome as well as by regulating their redox state. However, the role of circRNA in the regulation of serine/glycine metabolism has not been well elucidated.
METHODS: Microarray analysis was used to screen differentially expressed novel circRNAs. qRT-PCR and FISH were utilized to analyzed the expression of circMYH9. CCK8, colony formation and FACS were used to analyze proliferation of colorectal cancer (CRC) cells. Xenograft experiments were used to analyze tumor growth in vivo. RNA-sequencing, immunoblot and LC-MS were used to identify the downstream metabolic pathway of circMYH9. ChIRP, Mass Spectrometry, RIP and RNA pulldown were utilized to test the interaction between circMYH9, hnRNPA2B1 and p53 pre-mRNA. ChIP-qPCR was used to analyze the binding sites of HIF-1α. Chemically-induced CRC mice were generated to evaluate the role of circMYH9 in tumorigenesis.
RESULTS: We identified an intron-derived circRNA, circMYH9, which was significantly upregulated in CRC tissues. A higher circMYH9 level correlated with shorter relapse-free survival and overall survival of CRC patients. CircMYH9 promoted serine/glycine metabolism, the NAD + /NADH ratio, and glutathione recycling and inhibited reactive oxygen species (ROS) in a p53-dependent manner, impacting tumour growth. Mechanistically, circMYH9 destabilized the pre-mRNA of p53 by recruiting hnRNPA2B1 in the nucleus. hnRNPA2B1 bound to N6-methyladenosine sites on the 3' untranslated region of p53 pre-mRNA and maintained its stability. Moreover, a lack of amino acids led to an elevated level of ROS, resulting in increased HIF1α, which promoted circMYH9 expression by binding to the promoter region. Furthermore, in vivo AAV9-mediated transfection of circMYH9 could drive chemically-induced carcinogenesis by suppressing p53 in mice.
CONCLUSIONS: The overexpression of circMYH9 promotes CRC proliferation though modulating serine/glycine metabolism and redox homeostasis in a p53-dependent manner, and targeting circMYH9 and its pathway may be an effective strategy for the treatment of CRC.

Keywords:  Colorectal cancer; Redox homeostasis; Serine/glycine metabolism; circMYH9; p53

DOI:  https://doi.org/10.1186/s12943-021-01412-9
Oxid Med Cell Longev. 2021 ;2021 6545728

Cross-Talk between Oxidative Stress and m6A RNA Methylation in Cancer.

Baishuang Yang, Qiong Chen.

Oxidative stress is a state of imbalance between oxidation and antioxidation. Excessive ROS levels are an important factor in tumor development. Damage stimulation and excessive activation of oncogenes cause elevated ROS production in cancer, accompanied by an increase in the antioxidant capacity to retain redox homeostasis in tumor cells at an increased level. Although moderate concentrations of ROS produced in cancer cells contribute to maintaining cell survival and cancer progression, massive ROS accumulation can exert toxicity, leading to cancer cell death. RNA modification is a posttranscriptional control mechanism that regulates gene expression and RNA metabolism, and m6A RNA methylation is the most common type of RNA modification in eukaryotes. m6A modifications can modulate cellular ROS levels through different mechanisms. It is worth noting that ROS signaling also plays a regulatory role in m6A modifications. In this review, we concluded the effects of m6A modification and oxidative stress on tumor biological functions. In particular, we discuss the interplay between oxidative stress and m6A modifications.

DOI: https://doi.org/10.1155/2021/6545728
Pathol Res Pract. 2021 Aug 25. pii: S0344-0338(21)00256-9. [Epub ahead of print]226 153595

The role of glycometabolic plasticity in cancer.

Yuyang Peng, Hui Yang, Song Li.

  Dysregulated glycometabolism represented by the Warburg effect is well recognized as a hallmark of cancer that can be driven by oncogenes (e.g., c-Myc, K-ras, and BRAF) and contribute to cellular malignant transformation. The Warburg effect reveals the different glycometabolic patterns of cancer cells, but this unique glycometabolic pattern has the characteristic of plasticity rather than changeless which can vary with different internal or external stimuli during evolution. Glycometabolic plasticity enables cancer cells to modulate glycometabolism to support progression, metastasis, treatment resistance and recurrence. In this review, we report the characteristics of glycometabolic plasticity during different stages of cancer evolution, providing insight into the molecular mechanisms of glycometabolic plasticity in cancer. In addition, we discussed the challenges and future research directions of glycometabolism research in cancer.

Keywords:  Cancer; Glycometabolic plasticity; Metastasis; Treatment resistance

DOI:  https://doi.org/10.1016/j.prp.2021.153595
Cell Death Dis. 2021 Sep 04. 12(9): 832

Notch1/TAZ axis promotes aerobic glycolysis and immune escape in lung cancer.

Mian Xie, Xin-Ge Fu, Ke Jiang.

Oncogenic signaling pathway reprograms cancer cell metabolism to promote aerobic glycolysis in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T-cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. Notch1 signaling, dysregulated in lung cancer, is correlated with increased glycolysis. Herein, we demonstrate in lung cancer that Notch1 promotes glycolytic gene expression through functional interaction with histone acetyltransferases p300 and pCAF. Notch1 signaling forms a positive feedback loop with TAZ. Notch1 transcriptional activity was increased in the presence of TAZ and the activation was TEAD1 independent. Notably, aerobic glycolysis was critical for Notch1/TAZ axis modulation of lung cancer growth in vitro and in vivo. Increased level of extracellular lactate via Notch1/TAZ axis inhibited cytotoxic T-cell activity, leading to the invasive characteristic of lung cancer cells. Interaction between Notch1 and TAZ promoted aerobic glycolysis and immune escape in lung cancer. Our findings provide potential therapeutic targets against Notch1 and TAZ and would be important for clinical translation in lung cancer.

DOI: https://doi.org/10.1038/s41419-021-04124-6
Cancers (Basel). 2021 Aug 30. pii: 4375. [Epub ahead of print]13(17):

Targeting Amino Acid Metabolic Reprogramming via L-Type Amino Acid Transporter 1 (LAT1) for Endocrine-Resistant Breast Cancer.

Haruhiko Shindo, Narumi Harada-Shoji, Akiko Ebata, Miku Sato, Tomoyoshi Soga, Minoru Miyashita, Hiroshi Tada, Masaaki Kawai, Shinkichi Kosaka, Koji Onuki, Shin Usami, Shozo Furumoto, Shinichi Hayashi, Takaaki Abe, Takashi Suzuki, Takanori Ishida, Hironobu Sasano.

  The PI3K/Akt/mTOR pathway has been well known to interact with the estrogen receptor (ER)-pathway and to be also frequently upregulated in aromatase inhibitor (AI)-resistant breast cancer patients. Intracellular levels of free amino acids, especially leucine, regulate the mammalian target of rapamycin complex 1 (mTORC1) activation. L-type amino acid transporters such as LAT1 and LAT3 are associated with the uptake of essential amino acids. LAT1 expression could mediate leucine uptake, mTORC1 signaling, and cell proliferation. Therefore, in this study, we explored amino acid metabolism, including LAT1, in breast cancer and clarified the potential roles of LAT1 in the development of therapeutic resistance and the eventual clinical outcome of the patients. We evaluated LAT1 and LAT3 expression before and after neoadjuvant hormone therapy (NAH) and examined LAT1 function and expression in estrogen deprivation-resistant (EDR) breast carcinoma cell lines. Tumors tended to be in advanced stages in the cases whose LAT1 expression was high. LAT1 expression in the EDR cell lines was upregulated. JPH203, a selective LAT1 inhibitor, demonstrated inhibitory effects on cell proliferation in EDR cells. Hormone therapy changed the tumor microenvironment and resulted in metabolic reprogramming through inducing LAT1 expression. LAT1 expression then mediated leucine uptake, enhanced mTORC1 signaling, and eventually resulted in AI resistance. Therefore, LAT1 could be the potential therapeutic target in AI-resistant breast cancer patients.

Keywords:  JPH203; SLC43A1 (LAT3); SLC7A5 (LAT1); amino acid metabolism; breast cancer; hormone therapy

DOI:  https://doi.org/10.3390/cancers13174375
Cancer Cell Int. 2021 Sep 09. 21(1): 480

Current understanding of ferroptosis in the progression and treatment of pancreatic cancer.

Shi Dong, Xin Li, Wenkai Jiang, Zhou Chen, Wence Zhou.

  Pancreatic cancer is a highly malignant tumour of the digestive tract. Despite advances in treatment, its 5-year survival rate remains low, and its prognosis is the worst among all cancers; innovative therapeutic methods are needed. Ferroptosis is a form of regulatory cell death driven by iron accumulation and lipid peroxidation. Recent studies have found that ferroptosis plays an important role in the development and treatment response of tumours, particularly pancreatic cancer. This article reviews the current understanding of the mechanism of ferroptosis and ferroptosis-related treatment in pancreatic cancer.

Keywords:  Ferroptosis; Iron accumulation; Lipid peroxidation; Pancreatic cancer

DOI:  https://doi.org/10.1186/s12935-021-02166-6
Aging (Albany NY). 2021 Sep 07. 13(undefined):

Glutamine promotes escape from therapy-induced senescence in tumor cells.

Francesco Pacifico, Nadia Badolati, Stefano Mellone, Mariano Stornaiuolo, Antonio Leonardi, Elvira Crescenzi.

  Therapy-induced senescence (TIS) is a major cellular response to anticancer therapies. While induction of a persistent growth arrest would be a desirable outcome in cancer therapy, it has been shown that, unlike normal cells, cancer cells are able to evade the senescence cell cycle arrest and to resume proliferation, likely contributing to tumor relapse. Notably, cells that escape from TIS acquire a plastic, stem cell-like phenotype. The metabolic dependencies of cells that evade senescence have not been thoroughly studied. In this study, we show that glutamine depletion inhibits escape from TIS in all cell lines studied, and reduces the stem cell subpopulation. In line with a metabolic reliance on glutamine, escaped clones overexpress the glutamine transporter SLC1A5. We also demonstrate a central role of glutamine synthetase that mediates resistance to glutamine deprivation, conferring independence from exogenous glutamine. Finally, rescue experiments demonstrate that glutamine provides nitrogen for nucleotides biosynthesis in cells that escape from TIS, but also suggest a critical involvement of glutamine in other metabolic and non-metabolic pathways. On the whole, these results reveal a metabolic vulnerability of cancer stem cells that recover proliferation after exposure to anticancer therapies, which could be exploited to prevent tumor recurrence.

Keywords:  cancer stem cells; escape; glutamine; glutamine synthetase; therapy-induced senescence

DOI:  https://doi.org/10.18632/aging.203495
Cancer Cell Int. 2021 Sep 10. 21(1): 481

Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation.

Bo Cao, Huan Deng, Hao Cui, Ruiyang Zhao, Hanghang Li, Bo Wei, Lin Chen.

   BACKGROUND: Phosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism. However, the role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC.
METHODS: Correlation and enrichment analyses of PGM1 were conducted based on The Cancer Genome Atlas database. Data derived from the Kaplan-Meier Plotter database were analyzed to evaluate correlations between PGM1 expression and survival time of GC patients. Cell counting kit-8, 5-Ethynyl-2-deoxyuridine, flow cytometry assays, generation of subcutaneous tumor and lung metastasis mouse models were used to determine growth and metastasis in vitro and in vivo. Cell glycolysis was detected by a battery of glycolytic indicators, including lactate, pyruvic acid, ATP production and glucose uptake. Fatty Acid Synthase (FASN) activity and expression levels of lipid enzymes were determined to reflect on lipid metabolism.
RESULTS: Correlation and enrichment analyses suggested that PGM1 was closely associated with cell viability, proliferation and metabolism. PGM1 was overexpressed in GC tissues and cell lines. High PGM1 expression served as an indicator of shorter survival for specific subpopulation of GC patients. It was also correlated with pathological tumor stage and pathological tumor node metastasis stage of GC. Under the glucose deprivation condition, knockdown of PGM1 significantly suppressed cell viability, proliferation and glycolysis, whereas lipid metabolism was enhanced. Orlistat, as a drug that was designed to inhibit FASN activity, effectively induced apoptosis and suppressed lipid metabolism in GC. However, orlistat conversely increased glycolytic levels. Orlistat exhibited more significant inhibitive effects on GC progression after knockdown of PGM1 under glucose deprivation due to combination of glycolysis and lipid metabolism both in vitro and in vivo.
CONCLUSIONS: Downregulation of PGM1 expression under glucose deprivation enhanced anti-cancer effects of orlistat. This combination application may serve as a novel strategy for GC treatment.

Keywords:  Apoptosis; Cancer metabolism; Gastric cancer; Glucose deprivation; Orlistat; Phosphoglucomutase 1

DOI:  https://doi.org/10.1186/s12935-021-02193-3
Cancers (Basel). 2021 Sep 02. pii: 4426. [Epub ahead of print]13(17):

The Role of Oncogenes and Redox Signaling in the Regulation of PD-L1 in Cancer.

Christophe Glorieux, Xiaojun Xia, Peng Huang.

  Tumor cells can evade the immune system via multiple mechanisms, including the dysregulation of the immune checkpoint signaling. These signaling molecules are important factors that can either stimulate or inhibit tumor immune response. Under normal physiological conditions, the interaction between programmed cell death ligand 1 (PD-L1) and its receptor, programmed cell death 1 (PD-1), negatively regulates T cell function. In cancer cells, high expression of PD-L1 plays a key role in cancer evasion of the immune surveillance and seems to be correlated with clinical response to immunotherapy. As such, it is important to understand various mechanisms by which PD-L1 is regulated. In this review article, we provide an up-to-date review of the different mechanisms that regulate PD-L1 expression in cancer. We will focus on the roles of oncogenic signals (c-Myc, EML4-ALK, K-ras and p53 mutants), growth factor receptors (EGFR and FGFR), and redox signaling in the regulation of PD-L1 expression and discuss their clinical relevance and therapeutic implications. These oncogenic signalings have common and distinct regulatory mechanisms and can also cooperatively control tumor PD-L1 expression. Finally, strategies to target PD-L1 expression in tumor microenvironment including combination therapies will be also discussed.

Keywords:  PD-L1; ROS; cancer; combination therapy; growth factors; oncogenes; redox homeostasis

DOI:  https://doi.org/10.3390/cancers13174426
Lab Invest. 2021 Sep 09.

Anti-tumor effects of vitamin D in glioblastoma: mechanism and therapeutic implications.

Carmen Sze-Ching Lo, Karrie Mei-Yee Kiang, Gilberto Ka-Kit Leung.

Glioma is the most prevalent primary brain tumor in adults among which glioblastoma is the most malignant and lethal subtype. Its common resistance to conventional chemotherapeutics calls for the development of alternative or concomitant treatment. Taking advantage of its endocrine function as a neurosteroid, vitamin D has become a target of interest to be used in conjunction with different chemotherapies. In this article, we review the mechanisms through which vitamin D and its analogs induce anti-tumor activity in glioblastoma, and the practical issues relevant to their potential application based on in vitro and in vivo studies. Vitamin D has largely been reported to promote cell cycle arrest and induce cell death to suppress tumor growth in glioblastoma. Glioblastoma cells treated with vitamin D have also shown reduced migratory and invasive phenotypes, and reduced stemness. It is worth noting that vitamin D analogs are able to produce similar inhibitory actions without causing adverse effects such as hypercalcemia in vivo. Upregulation of vitamin D receptors by vitamin D and its analogs may also play a role in enhancing its anti-tumor activity. Based on current findings and taking into consideration its potential cancer-protective effects, the clinical application of vitamin D in glioblastoma treatment and prevention will be discussed. With some study findings subject to controversy, further investigation is warranted to elucidate the mechanism of action of vitamin D and to evaluate relevant issues regarding its treatment efficacy and potential clinical application.

DOI: https://doi.org/10.1038/s41374-021-00673-8
Anticancer Agents Med Chem. 2021 Aug 31.

A Comprehensive Review of the Use of Antioxidants and Natural Products in Cancer Patients Receiving Anticancer Therapy.

Daniel Sur, Alecsandra Gorzo, Shanthi Sabarimurugan, Saravana Murali Krishnan, Cristian Virgil Lungulescu, Simona Ruxandra Volovat, Claudia Burz.

  Cancer is the leading cause of mortality and morbidity worldwide. The side effects of cancer treatment affect the quality of life. Cancer patients search for antioxidant dietary supplements and natural products during or after conventional cancer treatment for the alleviation of side effects, improvement of the benefits of treatment, and promotion of well-being. However, the efficacy and safety of these products remain controversial; moreover, previous data do not support the standardized use of those alternative treatments in clinics. The current study reviewed the manuscripts reporting the administration of antioxidants and natural products during cancer treatment and revised preclinical and clinical studies on various types of cancer. Most of the positive results were obtained from experimental animal models; however, human clinical studies are discouraging in this regard. Therefore, further precise and distinguishable studies are required regarding antioxidant dietary supplementation. Future studies are also needed to clarify dietary supplements' mechanism of action and pharmacokinetics in a suitable cancer patient population that will benefit the therapeutic regimens. Despite the popularity of dietary supplements, clinicians and patients should always consider their potential benefits and risks. Patients should discuss with their physician before taking any dietary antioxidant supplements or natural products.

Keywords:  Antioxidants; cancer; chemotherapy; natural products; side effects; toxicity

DOI:  https://doi.org/10.2174/1871520621666210901100827
Cell Death Dis. 2021 Sep 04. 12(9): 835

The metabolic flexibility of quiescent CSC: implications for chemotherapy resistance.

Kangchen Chen, Chenzhi Zhang, Sunbin Ling, Rongli Wei, Jianguo Wang, Xiao Xu.

Quiescence has been observed in stem cells (SCs), including adult SCs and cancer SCs (CSCs). Conventional chemotherapies mostly target proliferating cancer cells, while the quiescent state favors CSCs escape to chemotherapeutic drugs, leaving risks for tumor recurrence or metastasis. The tumor microenvironment (TME) provides various signals that maintain resident quiescent CSCs, protect them from immune surveillance, and facilitates their recurrence potential. Since the TME has the potential to support and initiate stem cell-like programs in cancer cells, targeting the TME components may prove to be a powerful modality for the treatment of chemotherapy resistance. In addition, an increasing number of studies have discovered that CSCs exhibit the potential of metabolic flexibility when metabolic substrates are limited, and display increased robustness in response to stress. Accompanied by chemotherapy that targets proliferative cancer cells, treatments that modulate CSC quiescence through the regulation of metabolic pathways also show promise. In this review, we focus on the roles of metabolic flexibility and the TME on CSCs quiescence and further discuss potential treatments of targeting CSCs and the TME to limit chemotherapy resistance.

DOI: https://doi.org/10.1038/s41419-021-04116-6
Sci Rep. 2021 Sep 09. 11(1): 17925

RAS specific protease induces irreversible growth arrest via p27 in several KRAS mutant colorectal cancer cell lines.

Caleb K Stubbs, Marco Biancucci, Vania Vidimar, Karla J F Satchell.

Ras-specific proteases to degrade RAS within cancer cells are under active development as an innovative strategy to treat tumorigenesis. The naturally occurring biological toxin effector called RAS/RAP1-specific endopeptidase (RRSP) is known to cleave all RAS within a cell, including HRAS, KRAS, NRAS and mutant KRAS G13D. Yet, our understanding of the mechanisms by which RRSP drives growth inhibition are unknown. Here, we demonstrate, using isogenic mouse fibroblasts expressing a single isoform of RAS or mutant KRAS, that RRSP equally inactivates all isoforms of RAS as well as the major oncogenic KRAS mutants. To investigate how RAS processing might lead to varying outcomes in cell fate within cancer cells, we tested RRSP against four colorectal cancer cell lines with a range of cell fates. While cell lines highly susceptible to RRSP (HCT116 and SW1463) undergo apoptosis, RRSP treatment of GP5d and SW620 cells induces G1 cell cycle arrest. In some cell lines, growth effects were dictated by rescued expression of the tumor suppressor protein p27 (Kip1). The ability of RRSP to irreversibly inhibit cancer cell growth highlights the antitumor potential of RRSP, and further warrants investigation as a potential anti-tumor therapeutic.

DOI: https://doi.org/10.1038/s41598-021-97422-0
Molecules. 2021 Aug 24. pii: 5119. [Epub ahead of print]26(17):

α-Mangostin Nanoparticles Cytotoxicity and Cell Death Modalities in Breast Cancer Cell Lines.

Yedi Herdiana, Nasrul Wathoni, Shaharum Shamsuddin, Muchtaridi Muchtaridi.

  α-Mangostin (AMG) is a potent anticancer xanthone that was discovered in mangosteen (Garcinia mangostana Linn.). AMG possesses the highest opportunity for chemopreventive and chemotherapeutic therapy. AMG inhibits every step in the process of carcinogenesis. AMG suppressed multiple breast cancer (BC) cell proliferation and apoptosis by decreasing the creation of cancerous compounds. Accumulating BC abnormalities and their associated molecular signaling pathways promotes novel treatment strategies. Chemotherapy is a commonly used treatment; due to the possibility of unpleasant side effects and multidrug resistance, there has been substantial progress in searching for alternative solutions, including the use of plant-derived natural chemicals. Due to the limitations of conventional cancer therapy, nanotechnology provides hope for effective and efficient cancer diagnosis and treatment. Nanotechnology enables the delivery of nanoparticles and increased solubility of drugs and drug targeting, resulting in increased cytotoxicity and cell death during BC treatment. This review summarizes the progress and development of AMG's cytotoxicity and the mechanism of death BC cells. The combination of natural medicine and nanotechnology into a synergistic capital will provide various benefits. This information will aid in the development of AMG nanoparticle preparations and may open up new avenues for discovering an effective BC treatment.

Keywords:  AMG; apoptosis; breast cancer; cell death; cytotoxicity; nanotechnology

DOI:  https://doi.org/10.3390/molecules26175119
Cancer Cell Int. 2021 Sep 09. 21(1): 479

Role of glutamine and its metabolite ammonia in crosstalk of cancer-associated fibroblasts and cancer cells.

Xiao Li, Hongming Zhu, Weixuan Sun, Xingru Yang, Qing Nie, Xuedong Fang.

  Cancer-associated fibroblasts (CAFs), the most abundant cells in the tumor microenvironment, play an indispensable role in cancer initiation, progression, metastasis, and metabolism. The limitations of traditional treatments can be partly attributed to the lack of understanding of the role of the tumor stroma. For this reason, CAF targeting is gradually gaining attention, and many studies are trying to overcome the limitations of tumor treatment with CAF as a breakthrough. Glutamine (GLN) has been called a "nitrogen reservoir" for cancer cells because of its role in supporting anabolic processes such as fuel proliferation and nucleotide synthesis, but ammonia is a byproduct of the metabolism of GLN and other nitrogenous compounds. Moreover, in some studies, GLN has been reported as a fundamental nitrogen source that can support tumor biomass. In this review, we discuss the latest findings on the role of GLN and ammonia in the crosstalk between CAFs and cancer cells as well as the potential therapeutic implications of nitrogen metabolism.

Keywords:  Ammonia; Cancer cells; Cancer-associated fibroblasts; Glutamine; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12935-021-02121-5
Breast Cancer Res Treat. 2021 Sep 08.

Effects of PI3K inhibition in AI-resistant breast cancer cell lines: autophagy, apoptosis, and cell cycle progression.

Tiago V Augusto, Cristina Amaral, Yuanzhong Wang, Shiuan Chen, Cristina F Almeida, Natércia Teixeira, Georgina Correia-da-Silva.

   INTRODUCTION: Breast cancer is the leading cause of cancer death in women. The aromatase inhibitors (AIs), Anastrozole (Ana), Letrozole (Let), and Exemestane (Exe) are a first-line treatment option for estrogen receptor-positive (ER+) breast tumors, in postmenopausal women. Nevertheless, the development of acquired resistance to this therapy is a major drawback. The involvement of PI3K in resistance, through activation of the PI3K/AKT/mTOR survival pathway or through a cytoprotective autophagic process, is widely described.
MATERIALS AND METHODS: The involvement of autophagy in response to Ana and Let treatments and the effects of the combination of BYL-719, a PI3K inhibitor, with AIs were explored in AI-resistant breast cancer cell lines (LTEDaro, AnaR, LetR, and ExeR).
RESULTS: We demonstrate that Ana and Let treatments do not promote autophagy in resistant breast cancer cells, contrary to Exe. Moreover, the combinations of BYL-719 with AIs decrease cell viability by different mechanisms by nonsteroidal vs. steroidal AIs. The combination of BYL-719 with Ana or Let induced cell cycle arrest while the combination with Exe promoted cell cycle arrest and apoptosis. In addition, BYL-719 decreased AnaR, LetR, and ExeR cell viability in a dose- and time-dependent manner, being more effective in the ExeR cell line. This decrease was further exacerbated by ICI 182,780.
CONCLUSION: These results corroborate the lack of cross-resistance between AIs verified in the clinic, excluding autophagy as a mechanism of resistance to Ana or Let and supporting the ongoing clinical trials combining BYL-719 with AIs.

Keywords:  Acquired resistance; Aromatase inhibitors; Autophagy; BYL-719; Breast cancer

DOI:  https://doi.org/10.1007/s10549-021-06376-4
Cell Metab. 2021 Sep 07. pii: S1550-4131(21)00373-9. [Epub ahead of print]33(9): 1719-1720

T cells critically depend on pyruvate oxidation.

Christopher Schrecker, Andrew M Intlekofer.

Supporting the notion that cell lineage is a key determinant of cancer cell metabolism, Jun et al. (2021) identify a selective requirement for pyruvate dehydrogenase (PDH) activity in T cells and T cell leukemia, but not hematopoietic stem cells (HSCs) or myeloid leukemia, in this issue of Cell Metabolism.

DOI: https://doi.org/10.1016/j.cmet.2021.08.010
Cancers (Basel). 2021 Aug 24. pii: 4266. [Epub ahead of print]13(17):

Piperlongumine, a Potent Anticancer Phytotherapeutic, Induces Cell Cycle Arrest and Apoptosis In Vitro and In Vivo through the ROS/Akt Pathway in Human Thyroid Cancer Cells.

Fang-Ping Kung, Yun-Ping Lim, Wen-Ying Chao, Yi-Sheng Zhang, Hui-I Yu, Tsai-Sung Tai, Chieh-Hsiang Lu, Shu-Hsin Chen, Yi-Zhen Li, Pei-Wen Zhao, Yu-Pei Yen, Ying-Ray Lee.

  Thyroid cancer (TC) is the most common endocrine malignancy, and its global incidence has steadily increased over the past 15 years. TC is broadly divided into well-differentiated, poorly differentiated, and undifferentiated types, depending on the histological and clinical parameters. Thus far, there are no effective treatments for undifferentiated thyroid cancers or advanced and recurrent cancer. Therefore, the development of an effective therapeutic is urgently needed for such patients. Piperlongumine (PL) is a naturally occurring small molecule derived from long pepper; it is selectively toxic to cancer cells by generating reactive oxygen species (ROS). In this study, we demonstrate the potential anticancer activity of PL in four TC cell lines. For this purpose, we cultured TC cell lines and analyzed the following parameters: Cell viability, colony formation, cell cycle, apoptosis, and cellular ROS induction. PL modulated the cell cycle, induced apoptosis, and suppressed tumorigenesis in TC cell lines in a dose- and time-dependent manner through ROS induction. Meanwhile, an intrinsic caspase-dependent apoptosis pathway was observed in the TC cells under PL treatment. The activation of Erk and the suppression of the Akt/mTOR pathways through ROS induction were seen in cells treated with PL. PL-mediated apoptosis in TC cells was through the ROS-Akt pathway. Finally, the anticancer effect and safety of PL were also demonstrated in vivo. Our findings indicate that PL exhibits antitumor activity and has the potential for use as a chemotherapeutic agent against TC. This is the first study to show the sensitivity of TC cell lines to PL.

Keywords:  anaplastic thyroid cancer; effective treatment; novel therapeutic strategy; recurrent thyroid cancer; safe anticancer treatment

DOI:  https://doi.org/10.3390/cancers13174266
Front Oncol. 2021 ;11 675923

Curcumin as an Adjuvant to Cancer Immunotherapy.

Silpita Paul, Gaurisankar Sa.

  The components of the immune system play a very sincere and crucial role in combating tumors. However, despite their firm efforts of elimination, tumor cells cleverly escape the surveillance process by adopting several immune evasion mechanisms. The conversion of immunogenicity of tumor microenvironment into tolerogenic is considered as a prime reason for tumor immune escape. Therapeutically, different immunotherapies have been adopted to block such immune escaping routes along with better clinical outcomes. Still, the therapies are haunted by several drawbacks. Over time, curcumin has been considered as a potential anti-cancer molecule. Its potentialities have been recorded against the standard hallmarks of cancer such as continuous proliferation, escaping apoptosis, continuous angiogenesis, insensitivity to growth inhibitors, tissue invasion, and metastasis. Hence, the diversity of curcumin functioning has already been established and exploration of its application with immunotherapies might open up a new avenue for scientists and clinicians. In this review, we briefly discuss the tumor's way of immune escaping, followed by various modern immunotherapies that have been used to encounter the escaping paths and their minute flaws. Finally, the conclusion has been drawn with the application of curcumin as a potential immune-adjuvant, which fearlessly could be used with immunotherapies for best outcomes.

Keywords:  CTLA4; PD1/PD-L1; Treg cells; curcumin; dendritic cell; immune cells; immunotherapy

DOI:  https://doi.org/10.3389/fonc.2021.675923
World J Gastroenterol. 2021 Aug 14. 27(30): 4963-4984

Stress-activated kinases as therapeutic targets in pancreatic cancer.

Benno Traub, Aileen Roth, Marko Kornmann, Uwe Knippschild, Joachim Bischof.

  Pancreatic cancer is a dismal disease with high incidence and poor survival rates. With the aim to improve overall survival of pancreatic cancer patients, new therapeutic approaches are urgently needed. Protein kinases are key regulatory players in basically all stages of development, maintaining physiologic functions but also being involved in pathogenic processes. c-Jun N-terminal kinases (JNK) and p38 kinases, representatives of the mitogen-activated protein kinases, as well as the casein kinase 1 (CK1) family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors, DNA damage, and others. In their physiologic roles, they are responsible for the regulation of cell cycle progression, cell proliferation and differentiation, and apoptosis. Dysregulation of the underlying pathways consequently has been identified in various cancer types, including pancreatic cancer. Pharmacological targeting of those pathways has been the field of interest for several years. While success in earlier studies was limited due to lacking specificity and off-target effects, more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising in vitro results. Consequently, targeting of JNK, p38, and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases. However, further studies are warranted, especially involving in vivo investigation and clinical trials, in order to advance inhibition of stress-activated kinases to the field of translational medicine.

Keywords:  Casein kinase 1; Mitogen-activated protein kinases; Pancreatic cancer; Small molecule inhibitor; Stress-activated protein kinases; c-Jun N-terminal kinases

DOI:  https://doi.org/10.3748/wjg.v27.i30.4963
J Immunol Res. 2021 ;2021 9483433

A Perspective on Withania somnifera Modulating Antitumor Immunity in Targeting Prostate Cancer.

Seema Dubey, Manohar Singh, Ariel Nelson, Dev Karan.

Medicinal plants serve as a lead source of bioactive compounds and have been an integral part of day-to-day life in treating various disease conditions since ancient times. Withaferin A (WFA), a bioactive ingredient of Withania somnifera, has been used for health and medicinal purposes for its adaptogenic, anti-inflammatory, and anticancer properties long before the published literature came into existence. Nearly 25% of pharmaceutical drugs are derived from medicinal plants, classified as dietary supplements. The bioactive compounds in these supplements may serve as chemotherapeutic substances competent to inhibit or reverse the process of carcinogenesis. The role of WFA is appreciated to polarize tumor-suppressive Th1-type immune response inducing natural killer cell activity and may provide an opportunity to manipulate the tumor microenvironment at an early stage to inhibit tumor progression. This article signifies the cumulative information about the role of WFA in modulating antitumor immunity and its potential in targeting prostate cancer.

DOI: https://doi.org/10.1155/2021/9483433
Molecules. 2021 Aug 26. pii: 5163. [Epub ahead of print]26(17):

Impacting the Remedial Potential of Nano Delivery-Based Flavonoids for Breast Cancer Treatment.

Rakesh K Sindhu, Rishu Verma, Twinkle Salgotra, Md Habibur Rahman, Muddaser Shah, Rokeya Akter, Waheed Murad, Sidra Mubin, Parveen Bibi, Safaa Qusti, Eida M Alshammari, Gaber El-Saber Batiha, Michał Tomczyk, Hayder M Al-Kuraishy.

  Breast cancer persists as a diffuse source of cancer despite persistent detection and treatment. Flavonoids, a type of polyphenol, appear to be a productive option in the treatment of breast cancer, because of their capacity to regulate the tumor related functions of class of compounds. Plant polyphenols are flavonoids that appear to exhibit properties which are beneficial for breast cancer therapy. Numerous epidemiologic studies have been performed on the dynamic effect of plant polyphenols in the prevention of breast cancer. There are also subclasses of flavonoids that have antioxidant and anticarcinogenic activity. These can regulate the scavenging activity of reactive oxygen species (ROS) which help in cell cycle arrest and suppress the uncontrolled division of cancer cells. Numerous studies have also been performed at the population level, one of which reported a connection between cancer risk and intake of dietary flavonoids. Breast cancer appears to show intertumoral heterogeneity with estrogen receptor positive and negative cells. This review describes breast cancer, its various factors, and the function of flavonoids in the prevention and treatment of breast cancer, namely, how flavonoids and their subtypes are used in treatment. This review proposes that cancer risk can be reduced, and that cancer can be even cured by improving dietary intake. A large number of studies also suggested that the intake of fruit and vegetables is associated with reduced breast cancer and paper also includes the role and the use of nanodelivery of flavonoids in the healing of breast cancer. In addition, the therapeutic potential of orally administered phyto-bioactive compounds (PBCs) is narrowed because of poor stability and oral bioavailability of compounds in the gastrointestinal tract (GIT), and solubility also affects bioavailability. In recent years, creative nanotechnology-based approaches have been advised to enhance the activity of PBCs. Nanotechnology also offers the potential to become aware of disease at earlier stages, such as the detection of hidden or unconcealed metastasis colonies in patients diagnosed with lung, colon, prostate, ovarian, and breast cancer. However, nanoformulation-related effects and safety must not be overlooked. This review gives a brief discussion of nanoformulations and the effect of nanotechnology on herbal drugs.

Keywords:  anticancer; apoptosis; breast cancer; cancer therapeutics; drug delivery system; epidemiological study; flavonoids; nanoparticles; phytochemicals

DOI:  https://doi.org/10.3390/molecules26175163
Life Sci. 2021 Sep 04. pii: S0024-3205(21)00914-0. [Epub ahead of print] 119927

Ellagic acid-loaded, tween 80-coated, chitosan nanoparticles as a promising therapeutic approach against breast cancer: In-vitro and in-vivo study.

Harsheen Kaur, Sandip Ghosh, Pradeep Kumar, Biswarup Basu, Kalpana Nagpal.

   AIMS: Among polyphenolic phytoconstituents with anticancer properties, Ellagic acid (EA) is widely reported for its translational potential in vitro but efficient in vivo delivery of EA has been a challenge. We, for the first time, used a tween 80 coated nano delivery of Ellagic acid to evaluate its preclinical efficacy in vitro and in vivo for breast cancer.
MAIN METHODS: To overcome the challenges of in vivo delivery, two batches of chitosan-based nanoformulations of EA (with and without tween 80 coating) were prepared by the ionotropic gelation method. The nanoformulations were characterized and further evaluated in vitro against breast cancer cells (MCF7) and in vivo with EAC tumor-bearing mice for establishing their anticancer efficacy compared to Ellagic acid alone. A quantitative simulation study was undertaken to understand if the observed antitumor efficacy is due to the synergistic efficacy of the Chitosan-Ellagic acid combination.
KEY FINDINGS: Results revealed that nanoformulations consist of good nano-sized encapsulation of EA and showed good drug entrapment-release capacity. Nano-encapsulated EA is biocompatible and exhibited higher cytotoxicity in vitro compared to EA alone. Similarly, significantly higher tumor regression was observed in nano-EA treated mice compared to EA alone, and best efficacy was observed with the nanoformulation with tween 80 coating. Furthermore, nanoformulations showed higher apoptosis in tumor tissues with no significant tissue toxicity in vital organs.
SIGNIFICANCE: We report synergism of Chitosan-Ellagic acid combination in the tween 80 coated nanoparticles of Ellagic acid resulting in enhanced anti-breast tumor efficacy that may be of translational value for other tumor types, too.

Keywords:  Antitumor efficacy; Breast cancer; Chitosan nanoparticles; EAC; Ellagic acid; MCF7

DOI:  https://doi.org/10.1016/j.lfs.2021.119927
Sci Rep. 2021 Sep 06. 11(1): 17718

Metabolic rewiring is associated with HPV-specific profiles in cervical cancer cell lines.

Kalliopi I Pappa, George Daskalakis, Nicholas P Anagnou.

Both HPV-positive and HPV-negative cervical cancers are associated with aberrant metabolism, although the oncogenic drivers remain elusive. Here we show the assessment of the metabolomic profiles of four distinct cervical cell lines, a normal and three cancer cell lines, one HPV-negative (C33A) and two HPV-positive (SiHa HPV16+, HeLa HPV18+), employing an ultra performance liquid chromatography and a high resolution mass spectrometry. Out of the total 462 metabolites, 248 to 326 exhibited statistically significant differences, while Random Forests analysis identified unique molecules for each cell line. The two HPV+ cell lines exhibited features of Warburg metabolism, consistent with the role of the HPV E6 protein. SiHa and HeLa cells displayed purine salvage pathway activity, while C33A cells revealed synthesis of cytidine, via a novel mechanism. These data document a highly dynamic HPV-specific rewiring of metabolic pathways occurring in cervical cancer. Therefore, this approach can eventually provide novel mechanistic insights into cervical carcinogenesis.

DOI: https://doi.org/10.1038/s41598-021-96038-8
Anticancer Drugs. 2021 Aug 27.

Additive effects of resveratrol and doxorubicin on bladder cancer cells.

Luciana Bicalho Moreira Soares, Ana Paula Braga Lima, André Sacramento Melo, Tamires Cunha Almeida, Luiz Fernando de Medeiros Teixeira, Glenda Nicioli da Silva.

The treatment of bladder cancer remains a challenge in clinical practice. Different chemotherapeutic protocols can be used; however, it is common to observe tumor recurrence and secondary effects that result in toxicity. Doxorubicin (DOX), one of the most effective anticancer agents used to treat bladder cancer, can cause chronic cardiotoxicity, limiting its use in clinical practice. Resveratrol (RES), a natural product with potential antitumor activity against bladder cancer, is associated with rapid metabolism and low bioavailability and needs to be combined with chemotherapeutic drugs to improve its use. Our study aimed to assess the therapeutic effect of a low concentration of DOX (2 µM) in combination with RES (150, 200 and 250 µM) on two bladder cancer cell lines. We investigated the mechanism of interaction between the drugs by performing cytotoxicity, clonogenic, oxidative stress, cell migration, cell morphology and nuclear division index (NDI) assays. Cytotoxicity evaluation revealed an additive interaction between RES and DOX for both cell lines. Additionally, the results of cell colony formation, oxidative stress, cell migration, cell morphology and NDI assays showed that a combination of DOX and RES was more effective than RES or DOX alone. In conclusion, a low concentration of DOX combined with RES could potentiate the antitumor effects of the drugs on bladder cancer cells, thus overcoming the secondary effects caused by DOX and the low bioavailability of resveratrol.

DOI: https://doi.org/10.1097/CAD.0000000000001218
J Pharmacol Exp Ther. 2021 Sep 09. pii: JPET-AR-2021-000730. [Epub ahead of print]

Pharmacokinetic and Pharmacodynamic Assessment of Hydroxychloroquine in Breast Cancer.

Kristen M Van Eaton, Daniel L Gustafson.

  Hydroxychloroquine (HCQ) is being tested in a number of human clinical trials to determine the role of autophagy in response to standard anticancer therapies. However, HCQ pharmacodynamic responses are difficult to assess in patients and preclinical studies in mouse models are equivocal with regard to HCQ exposure and inhibition of autophagy. Here, pharmacokinetic (PK) assessment of HCQ in non-tumor bearing mice following intraperitoneal (IP) dosing established 60 mg/kg as the human equivalent dose of HCQ in mice. Autophagy inhibition, cell proliferation, and cell death were assessed in 2D cell culture and 3D tumor organoids in breast cancer. Mice challenged with breast cancer xenografts were then treated with 60 mg/kg HCQ via IP dosing and subsequent PK and pharmacodynamic (PD) responses were assessed. Although autophagic flux was significantly inhibited in cells irrespective of autophagy dependency status, autophagy dependent tumors had decreased cell proliferation and increased cell death at earlier time points compared to autophagy independent tumors. Overall, this study shows that 2D cell culture, 3D tumor organoids, and in vivo studies produce similar results and in vitro studies can be used as surrogates to recapitulate in vivo antitumor responses of HCQ. Significance Statement Autophagy dependent tumors, but not autophagy independent tumors, have decreased cell proliferation and increased cell death following single agent hydroxychloroquine treatment. However, hydroxychloroquine causes decreased autophagic flux regardless of autophagy status, suggesting its clinical efficacy in the context of autophagy inhibition.

Keywords:  Autophagy; breast cancer; cancer chemotherapy; pharmacodynamics; pharmacokinetics

DOI:  https://doi.org/10.1124/jpet.121.000730
Phytother Res. 2021 Sep 08.

Current clinical developments in curcumin-based therapeutics for cancer and chronic diseases.

Aviral Kumar, Choudhary Harsha, Dey Parama, Sosmitha Girisa, Uzini Devi Daimary, Xinliang Mao, Ajaikumar B Kunnumakkara.

  The last decade has seen an unprecedented rise in the prevalence of chronic diseases worldwide. Different mono-targeted approaches have been devised to treat these multigenic diseases, still most of them suffer from limited success due to the off-target debilitating side effects and their inability to target multiple pathways. Hence a safe, efficacious, and multi-targeted approach is the need for the hour to circumvent these challenging chronic diseases. Curcumin, a natural compound extracted from the rhizomes of Curcuma longa, has been under intense scrutiny for its wide medicinal and biological properties. Curcumin is known to manifest antibacterial, antiinflammatory, antioxidant, antifungal, antineoplastic, antifungal, and proapoptotic effects. A plethora of literature has already established the immense promise of curcuminoids in the treatment and clinical management of various chronic diseases like cancer, cardiovascular, metabolic, neurological, inflammatory, and infectious diseases. To date, more than 230 clinical trials have opened investigations to understand the pharmacological aspects of curcumin in human systems. Still, further randomized clinical studies in different ethnic populations warrant its transition to a marketed drug. This review summarizes the results from different clinical trials of curcumin-based therapeutics in the prevention and treatment of various chronic diseases.

Keywords:  bioavailability; chronic diseases; clinical trials; curcumin

DOI:  https://doi.org/10.1002/ptr.7264
Bioengineered. 2021 Dec;12(1): 6070-6082

Liquiritigenin exerts the anti-cancer role in oral cancer via inducing autophagy-related apoptosis through PI3K/AKT/mTOR pathway inhibition in vitro and in vivo.

Yingchen Ji, Weiwei Hu, Yan Jin, Huiming Yu, Jin Fang.

  Operative treatment on oral cancer greatly damages the chewing and language function of the patient, we aim to find better solution with fewer side effects. The anti-tumor effects of Liquiritigenin (LQ) have been explored in kinds of cancers, but not in oral cancer. In this study, our purpose is to reveal the effects of LQ on oral cancer and the associated mechanism.Cell proliferation was examined through 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and 5-Ethynyl-2'- deoxyuridine (EDU) staining. Cell apoptosis in cells and tissues were assessed by flow cytometry and terminal dexynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, respectively. Expressions of AKT and light chain 3 (LC3) were detected through Immunofluorescence. In addition, xenograft model was established by injecting the CAL-27 cells (2 × 106) subcutaneously into the right flanks of mice. Expression of Ki67 and Beclin1 in tissues was valued by Immunohistochemistry (IHC).We found that cell viability of CAL-27 and SCC-9 was effectively inhibited by LQ. Besides, obvious cell apoptosis and cell autophagy were induced by LQ. In addition, PI3K/AKT/mTOR pathway was sharply inactivated by LQ in oral cancer cells. Corresponding in vivo experiments demonstrated that tumor growth was largely restricted, cell apoptosis was augmented and autophagy was enhanced by LQ. What is more, phosphorylation of AKT in tumor tissues could also be inhibited by LQ. LQ inhibited the progression of oral cancer through inducing autophagy-associated apoptosis via PI3K/AKT/mTOR pathway inhibition, revealing a new possible scheme for the treatment of oral cancer.

Keywords:  Autophagy; apoptosis; oncology; oral cancer; signal pathway; traditional chinese medicine

DOI:  https://doi.org/10.1080/21655979.2021.1971501
Int J Pharm. 2021 Sep 06. pii: S0378-5173(21)00858-9. [Epub ahead of print] 121052

Ultrasound responsive self-assembled micelles loaded with hypocrellin for cancer sonodynamic therapy.

Xuexue Liu, Kai Zhao, Jin Cao, Xueyong Qi, Lin Wu, Song Shen.

  Nanoparticles have been demonstrated to be effective in targeted drug delivery to tumor due to the enhanced permeability and retention (EPR) effect. However, the inhomogeneous distribution of the nanoparticles in the tumor and the slow release of the drug make the therapeutic effect unsatisfied. Here, we present reactive oxygen species (ROS)-responsive micelles comprising poly (ethylene glycol)-poly(propylene sulfide) (PEG-PPS) for targeted delivery and in situ release of drug. Upon the irradiation of ultrasound, the loaded sonosensitizer hypocrellin (HC) will generate ROS to trigger the disassembly of the micelles and meanwhile realize sonodynamic therapy (SDT) effect of cancer. The in vivo experiment indicates that the HC loaded PEG-PPS are biocompatible and much more efficacious than an equivalent amount of free HC in inhibiting the growth of cancer.

Keywords:  ROS-responsive; hypocrellin; micelles; sonodynamic therapy; triggered drug release

DOI:  https://doi.org/10.1016/j.ijpharm.2021.121052
Molecules. 2021 Sep 02. pii: 5325. [Epub ahead of print]26(17):

Chemo-Preventive Action of Resveratrol: Suppression of p53-A Molecular Targeting Approach.

Rokeya Akter, Md Habibur Rahman, Deepak Kaushik, Vineet Mittal, Diana Uivarosan, Aurelia Cristina Nechifor, Tapan Behl, Chenmala Karthika, Manuela Stoicescu, Mihai Alexandru Munteanu, Cristiana Bustea, Simona Bungau.

  Extensive experimental, clinical, and epidemiological evidence has explained and proven that products of natural origin are significantly important in preventing and/or ameliorating various disorders, including different types of cancer that researchers are extremely focused on. Among these studies on natural active substances, one can distinguish the emphasis on resveratrol and its properties, especially the potential anticancer role. Resveratrol is a natural product proven for its therapeutic activity, with remarkable anti-inflammatory properties. Various other benefits/actions have also been reported, such as cardioprotective, anti-ageing, antioxidant, etc. and its rapid digestion/absorption as well. This review aims to collect and present the latest published studies on resveratrol and its impact on cancer prevention, molecular signals (especially p53 protein participation), and its therapeutic prospects. The most recent information regarding the healing action of resveratrol is presented and concentrated to create an updated database focused on this topic presented above.

Keywords:  cancer prevention; cardio protection; clinical trials; molecular signals; natural compound; p53; polyphenol; red wine; resveratrol

DOI:  https://doi.org/10.3390/molecules26175325
Expert Rev Precis Med Drug Dev. 2021 ;6(4): 281-294

Novel insights into the pathogenesis and treatment of NRAS mutant melanoma.

Jeffrey Zhao, Carlos Galvez, Kathryn Eby Beckermann, Douglas B Johnson, Jeffrey A Sosman.

   Introduction: NRAS was the first mutated oncogene identified in melanoma and is currently the second most common driver mutation in this malignancy. For patients with NRASmutant advanced stage melanoma refractory to immunotherapy or with contraindications to immune-based regimens, there are few therapeutic options including low-efficacy chemotherapy regimens and binimetinib monotherapy. Here, we review recent advances in preclinical studies of molecular targets for NRAS mutant melanoma as well as the failures and successes of early-phase clinical trials. While there are no targeted therapies for NRAS-driven melanoma, there is great promise in approaches combining MEK inhibition with inhibitors of the focal adhesion kinase (FAK), inhibitors of autophagy pathways, and pan-RAF inhibitors.
Areas Covered: This review surveys new developments in all aspects of disease pathogenesis and potential treatment - including those that have failed, stalled, or progressed through various phases of preclinical and clinical development.
Expert Opinion: There are no currently approved targeted therapies for BRAF wild-type melanoma patients harboring NRAS driver mutations though an array of agents are in early phase clinical trials. The diverse strategies taken exploit combined MAP kinase signaling blockade with inhibition of cell cycle mediators, inhibition of the autophagy pathway, and alteration of kinases involved in actin cytoskeleton signaling. Future advances of developmental therapeutics into late stage trials may yield new options beyond immunotherapy for patients with advanced stage disease and NRAS mutation status.

Keywords:  NRAS; clinical trials; drug development; genomics; melanocyte; melanoma; molecular genetics; oncology; pharmacology; precision medicine; targeted therapies; tumor biology

DOI:  https://doi.org/10.1080/23808993.2021.1938545