bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2023–01–15
28 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Nanocarrier Based Delivery of Berberine: A Critical Review on Pharmaceutical and Preclinical Characteristics of the Bioactive.
  2. Targeting cancer-specific metabolic pathways for developing novel cancer therapeutics.
  3. Overview of Cancer Metabolism and Signaling Transduction.
  4. Novel Strategies for the Bioavailability Augmentation and Efficacy Improvement of Natural Products in Oral Cancer.
  5. Lactic fermentation: A maladaptive mechanism and an evolutionary throwback boosting cancer drug resistance.
  6. The role of glutamine metabolism in castration-resistant prostate cancer.
  7. Synergistic Functional Nanomedicine Enhances Ferroptosis Therapy for Breast Tumors by a Blocking Defensive Redox System.
  8. Functionalized liposomes for targeted breast cancer drug delivery.
  9. A Novel Curcumin Arginine Salt: A Solution for Poor Solubility and Potential Anticancer Activities.
  10. Understanding the Contribution of Lactate Metabolism in Cancer Progress: A Perspective from Isomers.
  11. Enzyme and Reactive Oxygen Species-Responsive Dual-Drug Delivery Nanocomplex for Tumor Chemo-Photodynamic Therapy.
  12. Preparation and evaluation of paclitaxel-loaded reactive oxygen species and glutathione redox-responsive poly(lactic-co-glycolic acid) nanoparticles for controlled release in tumor cells.
  13. Impact of nanoparticles on amyloid beta-induced Alzheimer's disease, tuberculosis, leprosy and cancer: A systematic review.
  14. Recent Advances in the Role of Autophagy in Endocrine-Dependent Tumors.
  15. Metabolism in stem cell driven leukaemia: parallels between haematopoiesis and immunity.
  16. Molecular insights and therapeutic implications of nanoengineered dietary polyphenols for targeting lung carcinoma: part I.
  17. Overcoming cancer chemotherapy resistance by the induction of ferroptosis.
  18. Nano-ayurvedic medicine and its potential in cancer treatment.
  19. Molecular insights and therapeutic implications of nanoengineered dietary polyphenols for targeting lung cancer: part II.
  20. Activation of cancer immunotherapy by nanomedicine.
  21. The Effect of Oxidative Phosphorylation on Cancer Drug Resistance.
  22. Metabolic Adaptations of Cancer in Extreme Tumor Microenvironments.
  23. Formulation and development of novel lipid-based combinatorial advanced nanoformulation for effective treatment of non-melanoma skin cancer.
  24. Targeting the Nrf2 signaling pathway using phytochemical ingredients: A novel therapeutic road map to combat neurodegenerative diseases.
  25. Metabolic reprogramming and its clinical implication for liver cancer.
  26. Highly Biocompatible Apigenin-Loaded Silk Fibroin Nanospheres: Preparation, Characterization, and Anti-Breast-Cancer Activity.
  27. Development of Gastroretentive Carriers for Curcumin-Loaded Solid Dispersion Based on Expandable Starch/Chitosan Films.
  28. Fortified anti-proliferative activity of niclosamide for breast cancer treatment: In-vitro and in-vivo assessment.
  1. Curr Pharm Biotechnol. 2023 Jan 12.
    Nanocarrier Based Delivery of Berberine: A Critical Review on Pharmaceutical and Preclinical Characteristics of the Bioactive.
    Mohd Jawed Khan, Abdul Hafeez, Mohd Aftab Siddiqui.
      Berberine (BBR) is an isoquinoline alkaloid with several therapeutic properties, including anti-microbial, anti-diarrhea, anti-viral, anti-inflammatory, antihypertensive, anti-tumor, and anti-diabetes. However, its low water solubility, low absorption, first-pass metabolism, non-targeting, and poor bioavailability represent major hurdles to its successful therapeutic applications. Hence, researchers have attempted to enhance the biological and pharmacological activity of BBR to overcome its drawbacks by encapsulation of BBR in micro and nano delivery systems. For the preparation of nanostructured carrier systems of BBR, a range of methods has been developed, and each method has its benefits and characteristics. This review critically describes different types of nanocarriers like liposomes, niosomes, ethosomes, nanoemulsions, polymeric nanoparticles, micelles, dendrimers, and silver and gold nanoparticles that have been used for encapsulation of BBR for different therapeutic applications. The various pharmaceutical characteristics (size, shape, entrapment efficiency, zeta potential, drug release, and drug permeation) of these BBR-loaded nanocarriers have been discussed systematically. Preclinical studies of BBR nanoformulations involving animal models are also discussed.
    Keywords:  Berberine; Bioavailability enhancement; Nanocarrier; Nanotechnology; Sustained release; targeted delivery
    DOI:  https://doi.org/10.2174/1389201024666230112141330
  2. Front Immunol. 2022 ;13 955476
    Targeting cancer-specific metabolic pathways for developing novel cancer therapeutics.
    Soumik Pal, Amit Sharma, Sam Padalumavunkal Mathew, Bithiah Grace Jaganathan.
      Cancer is a heterogeneous disease characterized by various genetic and phenotypic aberrations. Cancer cells undergo genetic modifications that promote their proliferation, survival, and dissemination as the disease progresses. The unabated proliferation of cancer cells incurs an enormous energy demand that is supplied by metabolic reprogramming. Cancer cells undergo metabolic alterations to provide for increased energy and metabolite requirement; these alterations also help drive the tumor progression. Dysregulation in glucose uptake and increased lactate production via "aerobic glycolysis" were described more than 100 years ago, and since then, the metabolic signature of various cancers has been extensively studied. However, the extensive research in this field has failed to translate into significant therapeutic intervention, except for treating childhood-ALL with amino acid metabolism inhibitor L-asparaginase. Despite the growing understanding of novel metabolic alterations in tumors, the therapeutic targeting of these tumor-specific dysregulations has largely been ineffective in clinical trials. This chapter discusses the major pathways involved in the metabolism of glucose, amino acids, and lipids and highlights the inter-twined nature of metabolic aberrations that promote tumorigenesis in different types of cancer. Finally, we summarise the therapeutic interventions which can be used as a combinational therapy to target metabolic dysregulations that are unique or common in blood, breast, colorectal, lung, and prostate cancer.
    Keywords:  cancer; cancer metabolism; cancer microenvironment; metabolic reprogramming; targeted therapy
    DOI:  https://doi.org/10.3389/fimmu.2022.955476
  3. Int J Mol Sci. 2022 Dec 20. pii: 12. [Epub ahead of print]24(1):
    Overview of Cancer Metabolism and Signaling Transduction.
    Hee-Suk Chae, Seong-Tshool Hong.
      Despite the remarkable progress in cancer treatment up to now, we are still far from conquering the disease. The most substantial change after the malignant transformation of normal cells into cancer cells is the alteration in their metabolism. Cancer cells reprogram their metabolism to support the elevated energy demand as well as the acquisition and maintenance of their malignancy, even in nutrient-poor environments. The metabolic alterations, even under aerobic conditions, such as the upregulation of the glucose uptake and glycolysis (the Warburg effect), increase the ROS (reactive oxygen species) and glutamine dependence, which are the prominent features of cancer metabolism. Among these metabolic alterations, high glutamine dependency has attracted serious attention in the cancer research community. In addition, the oncogenic signaling pathways of the well-known important genetic mutations play important regulatory roles, either directly or indirectly, in the central carbon metabolism. The identification of the convergent metabolic phenotypes is crucial to the targeting of cancer cells. In this review, we investigate the relationship between cancer metabolism and the signal transduction pathways, and we highlight the recent developments in anti-cancer therapy that target metabolism.
    Keywords:  ROS; aerobic glycolysis; anti-cancer drug; cancer; glutamine; metabolism; redox; signal transduction
    DOI:  https://doi.org/10.3390/ijms24010012
  4. Cancers (Basel). 2022 Dec 30. pii: 268. [Epub ahead of print]15(1):
    Novel Strategies for the Bioavailability Augmentation and Efficacy Improvement of Natural Products in Oral Cancer.
    Alisha Sachdeva, Dimple Dhawan, Gaurav K Jain, Mükerrem Betül Yerer, Taylor E Collignon, Devesh Tewari, Anupam Bishayee.
      Oral cancer is emerging as a major cause of mortality globally. Oral cancer occupies a significant proportion of the head and neck, including the cheeks, tongue, and oral cavity. Conventional methods in the treatment of cancer involve surgery, radiotherapy, and immunotherapy, and these have not proven to completely eradicate cancerous cells, may lead to the reoccurrence of oral cancer, and possess numerous adverse side effects. Advancements in novel drug delivery approaches have gained popularity in cancer management with an increase in the number of cases associated with oral cancer. Natural products are potent sources for drug discovery, especially for anticancer drugs. Natural product delivery has major challenges due to its low solubility, poor absorption, inappropriate size, instability, poor permeation, and first-pass metabolism. Therefore, it is of prime importance to investigate novel treatment approaches for the delivery of bioactive natural products. Nanotechnology is an advanced method of delivering cancer therapy with minimal damage to normal cells while targeting cancer cells. Therefore, the present review elaborates on the advancements in novel strategies for natural product delivery that lead to the significant enhancement of bioavailability, in vivo activity, and fewer adverse events for the prevention and treatment of oral cancer. Various approaches to accomplish the desired results involve size reduction, surface property modification, and polymer attachment, which collectively result in the higher stability of the formulation.
    Keywords:  cancer; nanoparticles; natural products; oncogenes; oral cavity
    DOI:  https://doi.org/10.3390/cancers15010268
  5. Biochimie. 2023 Jan 10. pii: S0300-9084(23)00005-6. [Epub ahead of print]
    Lactic fermentation: A maladaptive mechanism and an evolutionary throwback boosting cancer drug resistance.
    Davide Gnocchi, Carlo Sabbà, Antonio Mazzocca.
      After four decades of research primarily focused on tumour genetics, the importance of metabolism in tumour biology is receiving renewed attention. Cancer cells undergo energy, biosynthetic and metabolic rewiring, which involves several pathways with a prevalent change from oxidative phosphorylation (OXPHOS) to lactic acid fermentation, known as the Warburg effect. During carcinogenesis, microenvironmental changes can trigger the transition from OXPHOS to lactic acid fermentation, an ancient form of energy supply, mimicking the behaviour of certain anaerobic unicellular organisms according to "atavistic" models of cancer. However, the role of this transition as a mechanism of cancer drug resistance is unclear. Here, we hypothesise that the metabolic rewiring of cancer cells to fermentation can be triggered, enhanced, and sustained by exposure to chronic or high-dose chemotherapy, thereby conferring resistance to drug therapy. We try to expand on the idea that metabolic reprogramming from OXPHOS to lactate fermentation in drug-resistant tumour cells occurs as a general phenotypic mechanism in any type of cancer, regardless of tumour cell heterogeneity, biodiversity, and genetic characteristics. This metabolic response may therefore represent a common feature in cancer biology that could be exploited for therapeutic purposes to overcome chemotherapy resistance, which is currently a major challenge in cancer treatment.
    Keywords:  Atavistic throwback; Drug resistance; Lactic acid fermentation; Maladaptive evolution; Metabolic switch
    DOI:  https://doi.org/10.1016/j.biochi.2023.01.005
  6. Asian J Androl. 2023 Jan 10.
    The role of glutamine metabolism in castration-resistant prostate cancer.
    Bing Zhao, Jing Wang, Li Chen, Hong Wang, Chao-Zhao Liang, Jiaoti Huang, Ling-Fan Xu.
      Reprogramming of metabolism is a hallmark of tumors, which has been explored for therapeutic purposes. Prostate cancer (PCa), particularly advanced and therapy-resistant PCa, displays unique metabolic properties. Targeting metabolic vulnerabilities in PCa may benefit patients who have exhausted currently available treatment options and improve clinical outcomes. Among the many nutrients, glutamine has been shown to play a central role in the metabolic reprogramming of advanced PCa. In addition to amino acid metabolism, glutamine is also widely involved in the synthesis of other macromolecules and biomasses. Targeting glutamine metabolic network by maximally inhibiting glutamine utilization in tumor cells may significantly add to treatment options for many patients. This review summarizes the metabolic landscape of PCa, with a particular focus on recent studies of how glutamine metabolism alterations affect therapeutic resistance and disease progression of PCa, and suggests novel therapeutic strategies.
    Keywords:  castration resistance; glutamine metabolism; prostate cancer; tumor metabolism
    DOI:  https://doi.org/10.4103/aja2022105
  7. ACS Appl Mater Interfaces. 2023 Jan 09.
    Synergistic Functional Nanomedicine Enhances Ferroptosis Therapy for Breast Tumors by a Blocking Defensive Redox System.
    Sijin Chen, Jing Yang, Zhiyu Liang, Zongheng Li, Wei Xiong, Qingdeng Fan, Zheyu Shen, Jianping Liu, Yikai Xu.
      The upregulation of dihydroorotate dehydrogenase (DHODH) redox systems inside tumor cells provides a powerful shelter against lipid peroxidation (LPO), impeding ferroptosis-induced antitumor responses. To solve this issue, we report a strategy to block redox systems and enhance ferroptotic cancer cell death based on a layered double hydroxide (LDH) nanoplatform (siR/IONs@LDH) co-loaded with ferroptosis agent iron oxide nanoparticles (IONs) and the DHODH inhibitor (siR). siR/IONs@LDH is able to simultaneously release IONs and siR in a pH-responsive manner, efficiently generate toxic reactive oxygen species (ROS) via an Fe2+-mediated Fenton reaction, and synergistically induce cancer cell death upon the acceleration of LPO accumulation. In vivo therapeutic evaluations demonstrate that this nanomedicine has excellent performance for tumor growth inhibition without any detectable side effects. This work thus provides a new insight into nanomaterial-mediated tumor ferroptosis therapy.
    Keywords:  DHODH inhibitor; ferroptosis; iron oxides nanoparticles; layered double hydroxide; lipid peroxidation
    DOI:  https://doi.org/10.1021/acsami.2c19585
  8. Bioact Mater. 2023 Jun;24 401-437
    Functionalized liposomes for targeted breast cancer drug delivery.
    Janske Nel, Kamil Elkhoury, Émilie Velot, Arnaud Bianchi, Samir Acherar, Grégory Francius, Ali Tamayol, Stéphanie Grandemange, Elmira Arab-Tehrany.
      Despite the exceptional progress in breast cancer pathogenesis, prognosis, diagnosis, and treatment strategies, it remains a prominent cause of female mortality worldwide. Additionally, although chemotherapies are effective, they are associated with critical limitations, most notably their lack of specificity resulting in systemic toxicity and the eventual development of multi-drug resistance (MDR) cancer cells. Liposomes have proven to be an invaluable drug delivery system but of the multitudes of liposomal systems developed every year only a few have been approved for clinical use, none of which employ active targeting. In this review, we summarize the most recent strategies in development for actively targeted liposomal drug delivery systems for surface, transmembrane and internal cell receptors, enzymes, direct cell targeting and dual-targeting of breast cancer and breast cancer-associated cells, e.g., cancer stem cells, cells associated with the tumor microenvironment, etc.
    Keywords:  Anti-cancer agents; Breast cancer; Liposomes; Receptor-targeted drug delivery; Surface functionalization; Targeted drug delivery
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.12.027
  9. Molecules. 2022 Dec 28. pii: 262. [Epub ahead of print]28(1):
    A Novel Curcumin Arginine Salt: A Solution for Poor Solubility and Potential Anticancer Activities.
    Adel Al Fatease, Mai E Shoman, Mohammed A S Abourehab, Heba A Abou-Taleb, Hamdy Abdelkader.
      Curcumin is a natural polyphenolic compound with well-known anticancer properties. Poor solubility and permeability hamper its use as an anticancer pharmaceutical product. In this study, L-arginine, a basic amino acid and a small hydrophilic molecule, was utilized to form a salt with the weak acid curcumin to enhance its solubility and potentiate the anticancer activities of curcumin. Two methods were adopted for the preparation of curcumin: L-arginine salt, namely, physical mixing and coprecipitation. The ion pair or salt was characterized for docking, solubility, DSC, FTIR, XRD, in vitro dissolution, and anticancer activities using MCF7 cell lines. The molecular docking suggested a salt/ion-pair complex between curcumin and L-arginine. Curcumin solubility was increased 335- and 440-fold by curcumin in L-arginine, physical, and co-precipitated mixtures, respectively. Thermal and spectral analyses supported the molecular docking and formation of a salt/ion pair between curcumin and L-arginine. The cytotoxicity of curcumin L-arginine salt significantly improved (p < 0.05) by 1.4-fold, as evidenced by the calculated IC50%, which was comparable to Taxol (the standard anticancer drug but with common side effects).
    Keywords:  L-arginine; breast cancer; curcumin; cytotoxicity
    DOI:  https://doi.org/10.3390/molecules28010262
  10. Cancers (Basel). 2022 Dec 23. pii: 87. [Epub ahead of print]15(1):
    Understanding the Contribution of Lactate Metabolism in Cancer Progress: A Perspective from Isomers.
    Ming Cai, Jian Wan, Keren Cai, Haihan Song, Yujiao Wang, Wanju Sun, Jingyun Hu.
      Lactate mediates multiple cell-intrinsic effects in cancer metabolism in terms of development, maintenance, and metastasis and is often correlated with poor prognosis. Its functions are undertaken as an energy source for neighboring carcinoma cells and serve as a lactormone for oncogenic signaling pathways. Indeed, two isomers of lactate are produced in the Warburg effect: L-lactate and D-lactate. L-lactate is the main end-production of glycolytic fermentation which catalyzes glucose, and tiny D-lactate is fabricated through the glyoxalase system. Their production inevitably affects cancer development and therapy. Here, we systematically review the mechanisms of lactate isomers production, and highlight emerging evidence of the carcinogenic biological effects of lactate and its isomers in cancer. Accordingly, therapy that targets lactate and its metabolism is a promising approach for anticancer treatment.
    Keywords:  D-lactate; L-lactate; anticancer therapy; cancer progression; lactate metabolism
    DOI:  https://doi.org/10.3390/cancers15010087
  11. Int J Nanomedicine. 2023 ;18 1-16
    Enzyme and Reactive Oxygen Species-Responsive Dual-Drug Delivery Nanocomplex for Tumor Chemo-Photodynamic Therapy.
    Qian Xie, Shi Gao, Rui Tian, Guohao Wang, Zainen Qin, Minglong Chen, Wenhui Zhang, Qiang Wen, Qingjie Ma, Lei Zhu.
       Introduction: Combination therapy is a promising approach to promote the efficacy and reduce the systemic toxicity of cancer therapy. Herein, we examined the potency of a combined chemo-phototherapy approach by constructing a hyaluronidase- and reactive oxygen species-responsive hyaluronic acid nanoparticle carrying a chemotherapy drug and a photosensitizer in a tumor-bearing mouse model. We hypothesized that following decomposition, the drugs inside the nanocomplex will be released in the tumors to provide effective tumor treatment. We aimed to design a smart drug delivery system that can improve traditional chemotherapy drug delivery and enhance the therapeutic efficacy in combination with photodynamic therapy.
    Methods: Hydrophilic hyaluronic acid (HA) was covalently modified with a hydrophobic 5β-cholanic acid (CA) via an ROS-cleavable thioketal (tk) linker for a targeted co-deliver of 10-Hydroxy camptothecin (HCPT) and Chlorin e6 (Ce6) into tumors to improve the efficiency of combined chemo-photodynamic therapy.
    Results: The obtained HA-tk-CA nanoparticle carrying HCPT and Ce6, named HTCC, accumulated in the tumor through the enhanced permeable response (EPR) effect and HA-mediated CD44 targeting after intravenous administration. Upon laser irradiation and hyaluronidase degradation, HTCC was disrupted to release HCPT and Ce6 into the tumors. Compared to the monotherapy approach, HTCC demonstrated enhanced tumor growth inhibition and minimized systemic toxicity in a tumor-bearing mouse model.
    Conclusion: Our results suggested that controlled dual-drug release not only improved tumor drug delivery efficacy, but also reduced systemic side effects. In addition to HCPT and Ce6 delivery, the HA-tk-CA nanocomplex can be used to deliver other drugs in synergistic cancer therapy. Since most current combined therapy uses free drugs with distinct spatiotemporal distributions, the simultaneous co-delivery of dual drugs with a remote on-demand drug delivery nanosystem provides an alternative strategy for drug delivery design.
    Keywords:  chemotherapy; drug delivery; hyaluronic acid; photodynamic therapy; responsive nanoparticle
    DOI:  https://doi.org/10.2147/IJN.S393862
  12. Nanomedicine (Lond). 2023 Jan 13.
    Preparation and evaluation of paclitaxel-loaded reactive oxygen species and glutathione redox-responsive poly(lactic-co-glycolic acid) nanoparticles for controlled release in tumor cells.
    Siying Wang, Feng Han, Lanlan Xie, Yanjie Liu, Qilei Yang, Dongmei Zhao, Xiuhua Zhao.
      Aim: To formulate and assess the anticancer effect of the poly(lactic-co-glycolic acid) (PLGA) copolymer with the thioether groups (diethyl sulfide [Des]) and disulfide bond (cystamine containing disulfide [Cys]), which encapsulated the anticancer drug paclitaxel (PTX) and triggered PTX release in cancer cell H2O2-rich or glutathione-rich surroundings. Methods: PLGA-b-P (Des@Cys) and PLGA-b-P nanoparticles loaded with PTX were prepared and characterized in vitro. The delivery ability of the PLGA-b-P nanoparticles and PLGA-b-P-PTX nanoparticles was assessed on a CT26 (mouse colon cancer cell line) and mouse lung cancer LLC model. Results: The nanoparticles were successfully prepared. Compared with free PTX, the formulated PLGA-b-P nanoparticles loaded with PTX exhibited greater accumulation at the tumor site in the mouse model. Conclusion: PLGA-b-P nanoparticles promote drug accumulation at tumor sites, providing an effective strategy for an intelligent, responsive drug-delivery system.
    Keywords:  GSH-sensitive; PLGA; ROS-sensitive; disulfide bond; dual-responsive nanoparticles; paclitaxel; polymer nanoparticles; targeted delivery; thioether bond; tumor microenvironment
    DOI:  https://doi.org/10.2217/nnm-2022-0164
  13. Biosci Rep. 2023 Jan 11. pii: BSR20220324. [Epub ahead of print]
    Impact of nanoparticles on amyloid beta-induced Alzheimer's disease, tuberculosis, leprosy and cancer: A systematic review.
    Ayon Chakraborty, Saswati Soumya Mohapatra, Subhashree Barik, Ipsita Roy, Bhavika Gupta, Ashis Biswas.
      Nanotechnology is an interdisciplinary domain of science, technology and engineering that deals with nano-sized materials/particles. Usually, the size of nanoparticles lies between 1-100 nm. Due to their small size and large surface area-to-volume ratio, nanoparticles exhibit high reactivity, greater stability and adsorption capacity. These important physicochemical properties attract scientific community to utilize them in biomedical field. Various types of nanoparticles (inorganic and organic) have broad applications in medical field ranging from imaging to gene therapy. These are also effective drug carriers. In recent times, nanoparticles are utilized to circumvent different treatment limitations. For example, the ability of nanoparticles to cross the blood brain barrier and having a certain degree of specificity towards amyloid deposits, makes themselves important candidates for the treatment of Alzheimer's disease. Furthermore, nanotechnology has been used extensively to overcome several pertinent issues like drug-resistance phenomenon, side effects of conventional drugs and targeted drug delivery issue in leprosy, tuberculosis and cancer. Thus, in this review, the application of different nanoparticles for the treatment of these four important diseases (Alzheimer's disease, tuberculosis, leprosy and cancer) as well as for the effective delivery of drugs used in these diseases has been presented systematically. Although nanoformulations have many advantages over traditional therapeutics for treating these diseases, nanotoxicity is a major concern which has been discussed subsequently. Lastly, we have presented the promising future prospective of nanoparticles as alternative therapeutics. In that section, we have discussed about the futuristic approach(es) that could provide promising candidate(s) for the treatment of these four diseases.
    Keywords:  Alzheimer's disease; Cancer; Drug delivery; Leprosy; Nanoparticles; Tuberculosis
    DOI:  https://doi.org/10.1042/BSR20220324
  14. Endocr Rev. 2023 Jan 12. pii: bnad001. [Epub ahead of print]
    Recent Advances in the Role of Autophagy in Endocrine-Dependent Tumors.
    Anvita Komarla, Suzanne Dufresne, Christina G Towers.
      Autophagy plays a complex role in several cancer types, including endocrine-dependent cancers, by fueling cellular metabolism and clearing damaged substrates. This conserved recycling process has a dual function across tumor types where it can be tumor suppressive at early stages but tumor promotional in established disease. This review highlights the controversial roles of autophagy in endocrine-dependent tumors regarding cancer initiation, tumorigenesis, metastasis, and treatment response. We summarize clinical trial results thus far and highlight the need for additional mechanistic, pre-clinical and clinical studies in endocrine-dependent tumors particularly in breast cancer and prostate cancer.
    Keywords:  Autophagy; Cancer; Chloroquine; Clinical trials; Endocrine-Dependent Tumors
    DOI:  https://doi.org/10.1210/endrev/bnad001
  15. Blood. 2023 Jan 12. pii: blood.2022018258. [Epub ahead of print]
    Metabolism in stem cell driven leukaemia: parallels between haematopoiesis and immunity.
    Kevin M Rattigan, Martha M Zarou, Vignir Helgason.
      Our understanding of cancer metabolism spans from its role in cellular energetics and supplying the building blocks necessary for proliferation, to maintaining cellular redox and regulating the cellular epigenome and transcriptome. Cancer metabolism, once thought to be solely driven by upregulated glycolysis, is now known to comprise of multiple pathways with great plasticity in response to extrinsic challenges. Furthermore, cancer cells can modify their surrounding niche during disease initiation, maintenance and metastasis, contributing to therapy resistance. Leukaemia is a paradigm model of stem cell driven cancer. Here, we review how leukaemia remodels the niche and rewires its metabolism with particular attention paid to therapy-resistant stem cells. Specifically, we aim to give a global, non-exhaustive overview of key metabolic pathways. By contrasting the metabolic rewiring required by myeloid leukaemic stem cells with that required for haematopoiesis and immune cell function, we highlight the metabolic features they share. This is a critical consideration when contemplating anti-cancer metabolic inhibitor options, especially in the context of anti-cancer immune therapies. Finally, we examine pathways that have not been studied in leukaemia but are critical in solid cancers in the context of metastasis and interaction with new niches. These studies also offer detailed mechanisms that have yet to be investigated in leukaemia. Given that cancer (and normal) cells can meet their energy requirements by not only upregulating metabolic pathways, but also utilising systemically available substrates, we aim to inform how interlinked these metabolic pathways are, both within leukaemic cells and between cancer cells and their niche.
    DOI:  https://doi.org/10.1182/blood.2022018258
  16. Nanomedicine (Lond). 2023 Jan 13.
    Molecular insights and therapeutic implications of nanoengineered dietary polyphenols for targeting lung carcinoma: part I.
    Sabya Sachi Das, Srushti Tambe, Priya Ranjan Prasad Verma, Purnima Amin, Neeru Singh, Sandeep Kumar Singh, Piyush Kumar Gupta.
      Lung cancer is the second leading cause of cancer-related mortality globally, and non-small-cell lung cancer accounts for most lung cancer cases. Nanotechnology-based drug-delivery systems have exhibited immense potential in lung cancer therapy due to their fascinating physicochemical characteristics, in vivo stability, bioavailability, prolonged and targeted delivery, gastrointestinal absorption and therapeutic efficiency of their numerous chemotherapeutic agents. However, traditional chemotherapeutics have systemic toxicity issues; therefore, dietary polyphenols might potentially replace them in lung cancer treatment. Polyphenol-based targeted nanotherapeutics have demonstrated interaction with a multitude of protein targets and cellular signaling pathways that affect major cellular processes. This review summarizes the various molecular mechanisms and targeted therapeutic potentials of nanoengineered dietary polyphenols in the effective management of lung cancer.
    Keywords:  lignans; lung cancer therapy; molecular mechanism; phenolic acids; stilbenes; targeted nanomedicine
    DOI:  https://doi.org/10.2217/nnm-2022-0133
  17. Drug Resist Updat. 2022 Dec 29. pii: S1368-7646(22)00115-7. [Epub ahead of print]66 100916
    Overcoming cancer chemotherapy resistance by the induction of ferroptosis.
    Yumin Wang, Xiaorui Wu, Zhao Ren, Yulin Li, Wailong Zou, Jichao Chen, Hongquan Wang.
      Development of resistance to chemotherapy in cancer continues to be a major challenge in cancer management. Ferroptosis, a unique type of cell death, is mechanistically and morphologically different from other forms of cell death. Ferroptosis plays a pivotal role in inhibiting tumour growth and has presented new opportunities for treatment of chemotherapy-insensitive tumours in recent years. Emerging studies have suggested that ferroptosis can regulate the therapeutic responses of tumours. Accumulating evidence supports ferroptosis as a potential target for chemotherapy resistance. Pharmacological induction of ferroptosis could reverse drug resistance in tumours. In this review article, we first discuss the key principles of chemotherapeutic resistance in cancer. We then provide a brief overview of the core mechanisms of ferroptosis in cancer chemotherapeutic drug resistance. Finally, we summarise the emerging data that supports the fact that chemotherapy resistance in different types of cancers could be subdued by pharmacologically inducing ferroptosis. This review article suggests that pharmacological induction of ferroptosis by bioactive compounds (ferroptosis inducers) could overcome chemotherapeutic drug resistance. This article also highlights some promising therapeutic avenues that could be used to overcome chemotherapeutic drug resistance in cancer.
    Keywords:  Bioactive compounds; Cancer; Chemotherapy; Drug resistance; Ferroptosis
    DOI:  https://doi.org/10.1016/j.drup.2022.100916
  18. J Integr Med. 2022 Dec 24. pii: S2095-4964(22)00125-X. [Epub ahead of print]
    Nano-ayurvedic medicine and its potential in cancer treatment.
    Manu Lopus.
      Nano-ayurvedic medicine is an emerging field in which nanoparticles are functionalized with active principles of potent ayurvedic herbs to enhance their efficacy and target-specific delivery. Scientific advances in the past couple of decades have revealed the molecular mechanisms behind the anticancer potential of several ayurvedic herbs, attributed chiefly to their secondary metabolites including polyphenols and other active substances. With the advancement of nanotechnology, it has been established that size-, shape-, and surface-chemistry-optimized nanoparticles can be utilized as synergizing carriers for these phytochemicals. Nano-ayurvedic medicine utilizes herbs that are commonly used in Ayurveda to functionalize different nanoparticles and thereby enhance their potency and target specificity. Studies have shown that the active phytochemicals of such herbs can be coated onto the nanoparticles of different metals, such as gold, and that they work more efficiently than the free herbal extract, for example, in inhibiting cancer cell proliferation. Recently, an Ayurveda, Yoga & Naturopathy, Unani, Siddha and Homeopathy (AYUSH)-based clinical trial in humans indicated the anticancer potential of such formulations. Nano-ayurvedic medicine is emerging as a potential treatment option for hyperproliferative diseases.
    Keywords:  Apoptosis; Cancer; Cell cycle; Nano-ayurvedic medicine; Nanomedicine
    DOI:  https://doi.org/10.1016/j.joim.2022.12.001
  19. Nanomedicine (Lond). 2023 Jan 13.
    Molecular insights and therapeutic implications of nanoengineered dietary polyphenols for targeting lung cancer: part II.
    Sabya Sachi Das, Srushti Tambe, Priya Ranjan Prasad Verma, Purnima Amin, Neeru Singh, Sandeep Kumar Singh, Piyush Kumar Gupta.
      Flavonoids represent a major group of polyphenolic compounds. Their capacity to inhibit tumor proliferation, cell cycle, angiogenesis, migration and invasion is substantially responsible for their chemotherapeutic activity against lung cancer. However, their clinical application is limited due to poor aqueous solubility, low permeability and quick blood clearance, which leads to their low bioavailability. Nanoengineered systems such as liposomes, nanoparticles, micelles, dendrimers and nanotubes can considerably enhance the targeted action of the flavonoids with improved efficacy and pharmacokinetic properties, and flavonoids can be successfully translated from bench to bedside through various nanoengineering approaches. This review addresses the therapeutic potential of various flavonoids and highlights the cutting-edge progress in the nanoengineered systems that incorporate flavonoids for treating lung cancer.
    Keywords:  flavonoids; lung cancer; molecular mechanisms; nanotherapeutics; targeted delivery systems
    DOI:  https://doi.org/10.2217/nnm-2022-0117
  20. Front Pharmacol. 2022 ;13 1041073
    Activation of cancer immunotherapy by nanomedicine.
    Lijuan Wang, Henan Xu, Lili Weng, Jin Sun, Ye Jin, Chunping Xiao.
      Cancer is one of the most difficult diseases to be treated in the world. Immunotherapy has made great strides in cancer treatment in recent years, and several tumor immunotherapy drugs have been approved by the U.S. Food and Drug Administration. Currently, immunotherapy faces many challenges, such as lacking specificity, cytotoxicity, drug resistance, etc. Nanoparticles have the characteristics of small particle size and stable surface function, playing a miraculous effect in anti-tumor treatment. Nanocarriers such as polymeric micelles, liposomes, nanoemulsions, dendrimers, and inorganic nanoparticles have been widely used to overcome deficits in cancer treatments including toxicity, insufficient specificity, and low bioavailability. Although nanomedicine research is extensive, only a few nanomedicines are approved to be used. Either Bottlenecks or solutions of nanomedicine in immunotherapy need to be further explored to cope with challenges. In this review, a brief overview of several types of cancer immunotherapy approaches and their advantages and disadvantages will be provided. Then, the types of nanomedicines, drug delivery strategies, and the progress of applications are introduced. Finally, the application and prospect of nanomedicines in immunotherapy and Chimeric antigen receptor T-cell therapy (CAR-T) are highlighted and summarized to address the problems of immunotherapy the overall goal of this article is to provide insights into the potential use of nanomedicines and to improve the efficacy and safety of immunotherapy.
    Keywords:  drug delivery; immunotherapy; nanoparticles; nanoparticles combined with CAR-T therapy; the CAR-T therapy
    DOI:  https://doi.org/10.3389/fphar.2022.1041073
  21. Cancers (Basel). 2022 Dec 22. pii: 62. [Epub ahead of print]15(1):
    The Effect of Oxidative Phosphorylation on Cancer Drug Resistance.
    Ziyi Zhao, Yong Mei, Ziyang Wang, Weiling He.
      Recent studies have shown that oxidative phosphorylation (OXPHOS) is a target for the effective attenuation of cancer drug resistance. OXPHOS inhibitors can improve treatment responses to anticancer therapy in certain cancers, such as melanomas, lymphomas, colon cancers, leukemias and pancreatic ductal adenocarcinoma (PDAC). However, the effect of OXPHOS on cancer drug resistance is complex and associated with cell types in the tumor microenvironment (TME). Cancer cells universally promote OXPHOS activity through the activation of various signaling pathways, and this activity is required for resistance to cancer therapy. Resistant cancer cells are prevalent among cancer stem cells (CSCs), for which the main metabolic phenotype is increased OXPHOS. CSCs depend on OXPHOS to survive targeting by anticancer drugs and can be selectively eradicated by OXPHOS inhibitors. In contrast to that in cancer cells, mitochondrial OXPHOS is significantly downregulated in tumor-infiltrating T cells, impairing antitumor immunity. In this review, we summarize novel research showing the effect of OXPHOS on cancer drug resistance, thereby explaining how this metabolic process plays a dual role in cancer progression. We highlight the underlying mechanisms of metabolic reprogramming in cancer cells, as it is vital for discovering new drug targets.
    Keywords:  cancer immunity; glycolysis; metabolism; oxidative phosphorylation; resistance
    DOI:  https://doi.org/10.3390/cancers15010062
  22. Cancer Sci. 2023 Jan 11.
    Metabolic Adaptations of Cancer in Extreme Tumor Microenvironments.
    Ryuichi Nakahara, Keisuke Maeda, Sho Aki, Tsuyoshi Osawa.
      Cancer cells are highly heterogeneous in order to adapt to extreme tumor microenvironments. Tumor microenvironments challenge cancer cells via hypoxia, nutrition starvation, and acidic pH, promoting invasion and metastasis concomitant with genetic, epigenetic, and metabolic alterations. Metabolic adaptation to an extreme tumor microenvironment could allow cancer cells to evade cell death and immune responses, as well as resulting in drug resistance, recurrence and poor patient prognosis. Therefore, elucidation of the metabolic adaptation of malignant cancer cells within tumor microenvironments is necessary, however, most are still elusive. Recently, adaptation of cancer cells within the tumor microenvironment can be analyzed via cell-cell interactions at the single cell level. In addition, information into organelle-organelle interactions has recently been obtained. These cell-cell, and organelle-organelle interactions demonstrate potential as new cancer therapy targets, as they play essential roles in the metabolic adaptation of cancer cells to the tumor microenvironment. In this manuscript, we review (1) metabolic adaptations within tumor microenvironments through (2) cell-to-cell, and (3) organelle-organelle metabolic interactions.
    Keywords:  Cancer Metabolism; Hypoxia; Nutrient starvation; Organelle; acidic pH
    DOI:  https://doi.org/10.1111/cas.15722
  23. Int J Pharm. 2023 Jan 03. pii: S0378-5173(22)01135-8. [Epub ahead of print]632 122580
    Formulation and development of novel lipid-based combinatorial advanced nanoformulation for effective treatment of non-melanoma skin cancer.
    Nazeer Hasan, Mohammad Imran, Masood Nadeem, Dhara Jain, Kashif Haider, M Moshahid Alam Rizvi, Afsana Sheikh, Prashant Kesharwani, Gaurav Kumar Jain, Farhan Jalees Ahmad.
      Non-melanoma skin cancer is one of the most common malignancies reported with high number of morbidities, demanding an advanced treatment option with superior chemotherapeutic effects. Due to high degree of drug resistance, conventional therapy fails to meet the desired therapeutic efficacy. To break the bottleneck, nanoparticles have been used as next generation vehicles that facilitate the efficient interaction with the cancer cells. Here, we developed combined therapy of 5-fluorouracil (5-FU) and cannabidiol (CBD)-loaded nanostructured lipid carrier gel (FU-CBD-NLCs gel). The NLCs were optimized using central composite design that showed an average particle size of 206 nm and a zeta potential of -34 mV. In addition, in vitro and ex vivo drug permeations studies demonstrated the effective delivery of both drugs in the skin layers via lipid structured nanocarriers. Also, the prepared FU-CBD-NLCs showed promising effect in-vitro cell studies including MTT assays, wound healing and cell cycle as compared to the conventional formulation. Moreover, dermatokinetic studies shows there was superior deposition of drugs at epidermal and the dermal layer when treated with FU-CBD-NLCs. In the end, overall study offered a novel combinatorial chemotherapy that could be an option for the treatment of non-melanoma skin cancer.
    Keywords:  5-Flurouracil; Cannabidiol; Combinatorial therapy; Dermal delivery; Nanoparticles; Non-melanoma skin cancer
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122580
  24. Phytomedicine. 2023 Jan;pii: S0944-7113(22)00670-5. [Epub ahead of print]109 154582
    Targeting the Nrf2 signaling pathway using phytochemical ingredients: A novel therapeutic road map to combat neurodegenerative diseases.
    Xue Bai, Zhigang Bian, Meng Zhang.
       BACKGROUND: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a classical nuclear transcription factor that regulates the system's anti-oxidative stress response. The activation of Nrf2 induces the expression of antioxidant proteins and improves the system's anti-oxidative stress ability. Accumulating evidence suggests that Nrf2-centered signaling pathways may be a key pharmacological target for the treatment of neurodegenerative diseases (NDDs). However, phytochemicals as new therapeutic agents against NDDs have not been clearly delineated.
    PURPOSE: To review the therapeutic effects of phytochemical ingredients on NDDs by activating Nrf2 and reducing oxidative stress injury.
    METHODS: A comprehensive search of published articles was performed using various literature databases including PubMed, Google Scholar, and China National Knowledge Infrastructure. The search terms included "Nrf2", "phytochemical ingredients", "natural bioactive agents", "neurodegenerative diseases", "Antioxidant", "Alzheimer's disease", "Parkinson's disease", "Huntington's disease", "amyotrophic lateral sclerosis" "multiple sclerosis", "toxicity", and combinations of these keywords. A total of 769 preclinical studies were retrieved until August 2022, and we included 39 of these articless on phytochemistry, pharmacology, toxicology and other fields.
    RESULTS: Numerous in vivo and in vitro studies showed that phytochemical ingredients could act as an Nrf2 activator in the treatment of NDDs through the antioxidant defense mechanism. These phytochemical ingredients, such as salidroside, naringenin, resveratrol, sesaminol, ellagic acid, ginsenoside Re, tanshinone I, sulforaphane, curcumin, naringin, tetramethylpyrazine, withametelin, magnolol, piperine, and myricetin, had the potential to improve Nrf2 signaling, thereby combatting NDDs.
    CONCLUSION: As Nrf2 activators, phytochemical ingredients may provide a novel potential strategy for the treatment of NDDs. Here, we reviewed the interaction between phytochemical ingredients, Nrf2, and its antioxidant damaging pathway in NDDs and explored the advantages of phytochemical ingredients in anti-oxidative stress, which provides a reliable basis for improving the treatment of NDDs. However, further clinical trials are needed to determine the safety and efficacy of Nrf2 activators for NDDs.
    Keywords:  Neurodegenerative diseases; Nrf2; Nrf2 activators; Oxidative stress; Phytochemical ingredients
    DOI:  https://doi.org/10.1016/j.phymed.2022.154582
  25. Hepatology. 2023 Jan 03.
    Metabolic reprogramming and its clinical implication for liver cancer.
    Flora Yang, Leena Hilakivi-Clarke, Aurpita Shaha, Yuanguo Wang, Xianghu Wang, Yibin Deng, Jinping Lai, Ningling Kang.
      Cancer cells often encounter hypoxic and hypo-nutrient conditions, which force them to make adaptive changes to meet their high demands for energy and various biomaterials for biomass synthesis. As a result, enhanced catabolism (breakdown of macromolecules for energy production) and anabolism (macromolecule synthesis from bio-precursors) are induced in cancer. This phenomenon is called "metabolic reprogramming", a cancer hallmark contributing to cancer development, metastasis, and drug resistance. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are two different liver cancers with high intertumoral heterogeneity in terms of etiologies, mutational landscapes, transcriptomes, and histological representations. In agreement, metabolism in HCC or CCA is remarkably heterogeneous, although changes in the glycolytic pathways and an increase in the generation of lactate (the Warburg effect) have been frequently detected in those tumors. For example, HCC tumors with activated β-catenin are addicted to fatty acid catabolism whereas HCC tumors derived from fatty liver avoid using fatty acids. In this review, we describe common metabolic alterations in HCC and CCA as well as metabolic features unique for their subsets. We discuss metabolism of non-alcoholic fatty liver disease (NAFLD) as well, because NAFLD will likely become a leading etiology of liver cancer in the coming years due to the obesity epidemic in the Western world. Furthermore, we outline the clinical implication of liver cancer metabolism and highlight the computation and systems biology approaches, such as genome-wide metabolic models, as a valuable tool allowing us to identify therapeutic targets and develop personalized treatments for liver cancer patients.
    DOI:  https://doi.org/10.1097/HEP.0000000000000005
  26. Polymers (Basel). 2022 Dec 21. pii: 23. [Epub ahead of print]15(1):
    Highly Biocompatible Apigenin-Loaded Silk Fibroin Nanospheres: Preparation, Characterization, and Anti-Breast-Cancer Activity.
    Weikun Qu, Peng Ji, Xibin Han, Xianglong Wang, Yang Li, Jin Liu.
      Breast cancer is among the most common fatal diseases among women. Low-toxicity apigenin (AGN) is of interest due to its good antitumor activity, but its clinical application is severely limited due to its poor water solubility and low bioavailability. An effective strategy to enhance the anti-breast-cancer activity of AGN is to develop it as a nanodelivery system. Silk fibroin (SF) is an ideal drug carrier with good biocompatibility, biodegradability, and a simple extraction process. This paper develops a novel and efficient apigenin-loaded silk fibroin nanodelivery system (SF-AGN) by nanoprecipitation with SF as a carrier. The system was characterized in terms of morphology, zeta potential, particle size, ultraviolet (UV), infrared (IR), and synchronous thermal analyses (TG-DSC), and the in vitro cytotoxicity and in vivo pharmacokinetics were examined. Finally, the chronic toxicity of SF-AGN in mice was studied. The SF-AGN nanodelivery system has good dispersibility, a hydrated particle size of 163.35 nm, a zeta potential of -18.5 mV, an average drug loading of 6.20%, and good thermal stability. MTT studies showed that SF-AGN significantly enhanced the inhibitory effect of AGN on 4T1 and MDA-MB-231 cells. Pharmacokinetic studies have demonstrated that SF-AGN can dramatically improve the bioavailability of AGN. The results of toxicity experiments showed that SF-AGN is biocompatible and does not alter normal tissues or organs. In sum, the SF-AGN nanodelivery system is a promising drug-delivery system for the clinical treatment of breast cancer.
    Keywords:  anti-breast-cancer; apigenin; pharmacokinetics; silk fibroin
    DOI:  https://doi.org/10.3390/polym15010023
  27. Molecules. 2023 Jan 01. pii: 361. [Epub ahead of print]28(1):
    Development of Gastroretentive Carriers for Curcumin-Loaded Solid Dispersion Based on Expandable Starch/Chitosan Films.
    Worrawee Siripruekpong, Ousanee Issarachot, Kanidta Kaewkroek, Ruedeekorn Wiwattanapatapee.
      Curcumin, a polyphenolic extract from the rhizomes of turmeric, exhibits antioxidant, anti-inflammatory, and anticancer activities, which are beneficial for the treatment of gastric diseases. However, curcumin's therapeutic usefulness is restricted by its low aqueous solubility and short gastric residence time. In this study, curcumin-loaded solid dispersion (ratio 1:5) was prepared using Eudragit® EPO (Cur EPO-SD), resulting in an approximately 12,000-fold increase in solubility to 6.38 mg/mL. Expandable films incorporating Cur EPO-SD were subsequently prepared by solvent casting using different types of starch (banana, corn, pregelatinized, and mung bean starch) in combination with chitosan. Films produced from banana, corn, pregelatinized and mung bean starch unfolded and expanded upon exposure to simulated gastric medium, resulting in sustained release of 80% of the curcumin content within 8 h, whereas films based on pregelatinized starch showed immediate release characteristics. Curcumin-loaded expandable films based on different types of starch exhibited similar cytotoxic effects toward AGS cells and more activity than unformulated curcumin. Furthermore, the films resulted in increased anti-inflammatory activity against RAW 264.7 macrophage cells compared with the NSAID, indomethacin. These findings demonstrate the potential of expandable curcumin-loaded films as gastroretentive dosage forms for the treatment of gastric diseases and to improve oral bioavailability.
    Keywords:  curcumin; expandable film; gastroretentive drug delivery system; solid dispersion; starch
    DOI:  https://doi.org/10.3390/molecules28010361
  28. Life Sci. 2023 Jan 06. pii: S0024-3205(23)00013-9. [Epub ahead of print] 121379
    Fortified anti-proliferative activity of niclosamide for breast cancer treatment: In-vitro and in-vivo assessment.
    Amira Mansour, Mohamed Y Mahmoud, Alaa F Bakr, Monira G Ghoniem, Fatima A Adam, Ibrahim M El-Sherbiny.
      Breast cancer represents one of the top lethal cancer types among the females worldwide. Several factors manipulate the clinical outcome of the treatment as the stage of the cancer upon detection, genetic and hormonal factors, drug resistance and metastasis. Accordingly, drug's repositioning, enhancing the bioavailability and encapsulation into nanoparticles (NPs) are among the predilected pathways for enhanced therapeutic outcome. Niclosamide (NIC) is an anthelmintic drug and has been repositioned as anticancer agent after revealing its anti-neoplastic activity. Piperine (PIP) was used as food spice until its anticancer activity was discovered. However, their hydrophobicity constrains their therapeutic efficiency. The cytotoxicity of both drugs in the free form was tested on MCF-7 cells, and the results indicated a NIC cytotoxicity enhancement by PIP. Then, NIC and PIP were encapsulated successfully into F127-NPs with entrapment efficiency of 97 % and 82 %, respectively. Particle size, zeta potential, TEM and FTIR confirmed the micellization process and drug encapsulation. The developed NIC-NPs and PIP-NPs exerted potent anticancer effect as compared to the free forms. Accordingly, the mixture; NIC-NPs/PIP-NPs was tested and its cytotoxicity exceeded the individually encapsulated drugs. Flowcytometry assessment was performed and demonstrated an induced cell death through the apoptotic stage. Additionally, in-vivo therapeutic efficiency of NIC-NPs/PIP-NPs was assessed through Ehrlich ascites tumor and the nanocombination therapy exerted superior additive anticancer effect when compared to NIC-NPs which is attributed to the PIP-NPs induced bioavailability. The study can be considered the first one investigating the PIP role in bioenhancing the anti-proliferative activity of NIC to combat breast cancer.
    Keywords:  Anti-proliferative activity; Bioenhancer; Nanoparticles; Niclosamide; Piperine; Pluronic
    DOI:  https://doi.org/10.1016/j.lfs.2023.121379
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