Journal articles on the topic 'Drug resistance in cancer cells'
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1
Cho, Heyrim, and Doron Levy. "The impact of competition between cancer cells and healthy cells on optimal drug delivery." Mathematical Modelling of Natural Phenomena 15 (2020): 42. http://dx.doi.org/10.1051/mmnp/2019043.
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Cell competition is recognized to be instrumental to the dynamics and structure of the tumor-host interface in invasive cancers. In mild competition scenarios, the healthy tissue and cancer cells can coexist. When the competition is aggressive, competitive cells, the so called super-competitors, expand by killing other cells. Novel chemotherapy drugs and molecularly targeted drugs are commonly administered as part of cancer therapy. Both types of drugs are susceptible to various mechanisms of drug resistance, obstructing or preventing a successful outcome. In this paper, we develop a cancer growth model that accounts for the competition between cancer cells and healthy cells. The model incorporates resistance to both chemotherapy and targeted drugs. In both cases, the level of drug resistance is assumed to be a continuous variable ranging from fully-sensitive to fully-resistant. Using our model we demonstrate that when the competition is moderate, therapies using both drugs are more effective compared with single drug therapies. However, when cancer cells are highly competitive, targeted drugs become more effective. The results of the study stress the importance of adjusting the therapy to the pre-treatment resistance levels. We conclude with a study of the spatiotemporal propagation of drug resistance in a competitive setting, verifying that the same conclusions hold in the spatially heterogeneous case.
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Zhao, Ziyi, Yong Mei, Ziyang Wang, and Weiling He. "The Effect of Oxidative Phosphorylation on Cancer Drug Resistance." Cancers 15, no. 1 (December 22, 2022): 62. http://dx.doi.org/10.3390/cancers15010062.
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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.
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NM, Nandini. "Cancer Stem Cells and Drug Resistance." Acta Scientific Cancer Biology 4, no. 6 (May 27, 2020): 12–18. http://dx.doi.org/10.31080/ascb.2020.04.0228.
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Marx, J. "Drug resistance of cancer cells probed." Science 234, no. 4778 (November 14, 1986): 818–20. http://dx.doi.org/10.1126/science.2877493.
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Leary, Meghan, Sarah Heerboth, Karolina Lapinska, and Sibaji Sarkar. "Sensitization of Drug Resistant Cancer Cells: A Matter of Combination Therapy." Cancers 10, no. 12 (December 4, 2018): 483. http://dx.doi.org/10.3390/cancers10120483.
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Cancer drug resistance is an enormous problem. It is responsible for most relapses in cancer patients following apparent remission after successful therapy. Understanding cancer relapse requires an understanding of the processes underlying cancer drug resistance. This article discusses the causes of cancer drug resistance, the current combination therapies, and the problems with the combination therapies. The rational design of combination therapy is warranted to improve the efficacy. These processes must be addressed by finding ways to sensitize the drug-resistant cancers cells to chemotherapy, and to prevent formation of drug resistant cancer cells. It is also necessary to prevent the formation of cancer progenitor cells by epigenetic mechanisms, as cancer progenitor cells are insensitive to standard therapies. In this article, we emphasize the role for the rational development of combination therapy, including epigenetic drugs, in achieving these goals.
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Wtorek, Karol, Angelika Długosz, and Anna Janecka. "Drug resistance in topoisomerase-targeting therapy." Postępy Higieny i Medycyny Doświadczalnej 72 (December 21, 2018): 1073–83. http://dx.doi.org/10.5604/01.3001.0012.8131.
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Drug resistance is a well-known phenomenon that occurs when initially responsive to chemotherapy cancer cells become tolerant and elude further effectiveness of anticancer drugs. Based on their mechanism of action, anticancer drugs can be divided into cytotoxic-based agents and target-based agents. An important role among the therapeutics of the second group is played by drugs targeting topoisomerases, nuclear enzymes critical to DNA function and cell survival. These enzymes are cellular targets of several groups of anticancer agents which generate DNA damage in rapidly proliferating cancer cells. Drugs targeting topoisomerase I are mostly analogs of camtothecin, a natural compound isolated from the bark of a tree growing in China. Drugs targeting topoisomerase II are divided into poisons, such as anthracycline antibiotics, whose action is based on intercalation between DNA bases, and catalytic inhibitors that block topoisomerase II at different stages of the catalytic cycle. Unfortunately, chemotherapy is often limited by the induction of drug resistance. Identifying mechanisms that promote drug resistance is critical for the improvement of patient prognosis. Cancer drug resistance is a complex phenomenon that may be influenced by many factors. Here we discuss various mechanisms by which cancer cells can develop resistance to topoisomerase-directed drugs, which include enhanced drug efflux, mutations in topoisomerase genes, hypophosphorylation of topoisomerase II catalytic domain, activation of NF-κB transcription factor and drug inactivation. All these events may lead to the ineffective induction of cancer cell death. Attempts at circumventing drug resistance through the inhibition of cellular efflux pumps, use of silencing RNAs or inhibition of some important mechanisms, which can allow cancer cells to survive therapy, are also presented.
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Altamura, Concetta, Paola Gavazzo, Michael Pusch, and Jean-François Desaphy. "Ion Channel Involvement in Tumor Drug Resistance." Journal of Personalized Medicine 12, no. 2 (February 3, 2022): 210. http://dx.doi.org/10.3390/jpm12020210.
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Over 90% of deaths in cancer patients are attributed to tumor drug resistance. Resistance to therapeutic agents can be due to an innate property of cancer cells or can be acquired during chemotherapy. In recent years, it has become increasingly clear that regulation of membrane ion channels is an important mechanism in the development of chemoresistance. Here, we review the contribution of ion channels in drug resistance of various types of cancers, evaluating their potential in clinical management. Several molecular mechanisms have been proposed, including evasion of apoptosis, cell cycle arrest, decreased drug accumulation in cancer cells, and activation of alternative escape pathways such as autophagy. Each of these mechanisms leads to a reduction of the therapeutic efficacy of administered drugs, causing more difficulty in cancer treatment. Thus, targeting ion channels might represent a good option for adjuvant therapies in order to counteract chemoresistance development.
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De Conti, Giulia, Matheus Henrique Dias, and René Bernards. "Fighting Drug Resistance through the Targeting of Drug-Tolerant Persister Cells." Cancers 13, no. 5 (March 5, 2021): 1118. http://dx.doi.org/10.3390/cancers13051118.
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Designing specific therapies for drug-resistant cancers is arguably the ultimate challenge in cancer therapy. While much emphasis has been put on the study of genetic alterations that give rise to drug resistance, much less is known about the non-genetic adaptation mechanisms that operate during the early stages of drug resistance development. Drug-tolerant persister cells have been suggested to be key players in this process. These cells are thought to have undergone non-genetic adaptations that enable survival in the presence of a drug, from which full-blown resistant cells may emerge. Such initial adaptations often involve engagement of stress response programs to maintain cancer cell viability. In this review, we discuss the nature of drug-tolerant cancer phenotypes, as well as the non-genetic adaptations involved. We also discuss how malignant cells employ homeostatic stress response pathways to mitigate the intrinsic costs of such adaptations. Lastly, we discuss which vulnerabilities are introduced by these adaptations and how these might be exploited therapeutically.
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Puris, Elena, Gert Fricker, and Mikko Gynther. "The Role of Solute Carrier Transporters in Efficient Anticancer Drug Delivery and Therapy." Pharmaceutics 15, no. 2 (January 21, 2023): 364. http://dx.doi.org/10.3390/pharmaceutics15020364.
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Transporter-mediated drug resistance is a major obstacle in anticancer drug delivery and a key reason for cancer drug therapy failure. Membrane solute carrier (SLC) transporters play a crucial role in the cellular uptake of drugs. The expression and function of the SLC transporters can be down-regulated in cancer cells, which limits the uptake of drugs into the tumor cells, resulting in the inefficiency of the drug therapy. In this review, we summarize the current understanding of low-SLC-transporter-expression-mediated drug resistance in different types of cancers. Recent advances in SLC-transporter-targeting strategies include the development of transporter-utilizing prodrugs and nanocarriers and the modulation of SLC transporter expression in cancer cells. These strategies will play an important role in the future development of anticancer drug therapies by enabling the efficient delivery of drugs into cancer cells.
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Valinezhad Sani, Fatemeh, Abbasali Palizban, Fatemeh Mosaffa, and Khadijeh Jamialahmadi. "Glucosamine attenuates drug resistance in Mitoxantrone-resistance breast cancer cells." Journal of Pharmacy and Pharmacology 73, no. 7 (April 22, 2021): 922–27. http://dx.doi.org/10.1093/jpp/rgaa032.
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Abstract Objectives This study was aimed at investigating the cytotoxicity and multi-drug resistance (MDR) reversal effect of Glucosamine (GlcN) on resistant BCRP-overexpressing breast cancer MCF-7/MX cells. Methods After confirming the overexpression of BCRP, the cytotoxicity and MDR reversing potential of GlcN on MCF-7/MX mitoxantrone-resistant and MCF-7 sensitive breast cancer cells were assessed via MTT assay. The effects of GlcN on mitoxantrone accumulation were analyzed through flow cytometry. Finally, the expression of BCRP and Epithelial-Mesenchymal Transition (EMT)-related markers following the exposure to GlcN were assessed by real-time RT-PCR. Key findings This study showed that glucosamine had an inhibitory effect on the proliferation of human breast cancer cells. The respective IC50 values for MCF-7/MX cells following exposure to mitoxantrone (MX) in the presence of GlcN (0, 0.5 and 1 mm) for 72 h were 3.61 ± 0.21, 0.598 ± 0.041 and 0.284 ± 0.016 μm, respectively. Furthermore, GlcN reduced the expression of BCRP mRNA without any significant effect on EMT-related markers in breast cancer cells. Conclusions These results proposed that glucosamine as a natural sugar could down regulate the BCRP expression and increased MX cytotoxicity in breast cancer cells.
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Smith, Alexandra G., and Kay F. Macleod. "Autophagy, cancer stem cells and drug resistance." Journal of Pathology 247, no. 5 (February 4, 2019): 708–18. http://dx.doi.org/10.1002/path.5222.
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An, Junsha, Cheng Peng, Hailin Tang, Xiuxiu Liu, and Fu Peng. "New Advances in the Research of Resistance to Neoadjuvant Chemotherapy in Breast Cancer." International Journal of Molecular Sciences 22, no. 17 (September 6, 2021): 9644. http://dx.doi.org/10.3390/ijms22179644.
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Breast cancer has an extremely high incidence in women, and its morbidity and mortality rank first among female tumors. With the increasing development of medicine today, the clinical application of neoadjuvant chemotherapy has brought new hope to the treatment of breast cancer. Although the efficacy of neoadjuvant chemotherapy has been confirmed, drug resistance is one of the main reasons for its treatment failure, contributing to the difficulty in the treatment of breast cancer. This article focuses on multiple mechanisms of action and expounds a series of recent research advances that mediate drug resistance in breast cancer cells. Drug metabolizing enzymes can mediate a catalytic reaction to inactivate chemotherapeutic drugs and develop drug resistance. The drug efflux system can reduce the drug concentration in breast cancer cells. The combination of glutathione detoxification system and platinum drugs can cause breast cancer cells to be insensitive to drugs. Changes in drug targets have led to poorer efficacy of HER2 receptor inhibitors. Moreover, autophagy, epithelial–mesenchymal transition, and tumor microenvironment can all contribute to the development of resistance in breast cancer cells. Based on the relevant research on the existing drug resistance mechanism, the current treatment plan for reversing the resistance of breast cancer to neoadjuvant chemotherapy is explored, and the potential drug targets are analyzed, aiming to provide a new idea and strategy to reverse the resistance of neoadjuvant chemotherapy drugs in breast cancer.
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Zhai, Zili, Jenny Mae Samson, Takeshi Yamauchi, Prasanna K. Vaddi, Yuko Matsumoto, Charles A. Dinarello, Dinoop Ravindran Menon, and Mayumi Fujita. "Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma." Cancers 12, no. 9 (September 4, 2020): 2518. http://dx.doi.org/10.3390/cancers12092518.
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Cancer cells gain drug resistance through a complex mechanism, in which nuclear factor-κB (NF-κB) and interleukin-1β (IL-1β) are critical contributors. Because NACHT, LRR and PYD domains-containing protein (NLRP) inflammasomes mediate IL-1β maturation and NF-κB activation, we investigated the role of inflammasome sensor NLRP1 in acquired drug resistance to temozolomide (TMZ) in melanoma. The sensitivity of melanoma cells to TMZ was negatively correlated with the expression levels of O6-methylguanine-DNA methyltransferase (MGMT), the enzyme to repair TMZ-induced DNA lesions. When MGMT-low human melanoma cells (1205Lu and HS294T) were treated with TMZ for over two months, MGMT was upregulated, and cells became resistant. However, the resistance mechanism was independent of MGMT, and the cells that acquired TMZ resistance showed increased NLRP1 expression, NLRP inflammasome activation, IL-1β secretion, and NF-κB activity, which contributed to the acquired resistance to TMZ. Finally, blocking IL-1 receptor (IL-1R) signaling with IL-1R antagonist decreased TMZ-resistant 1205Lu tumor growth in vivo. Although inflammation has been associated with drug resistance in various cancers, our paper is the first to demonstrate the involvement of NLRP in the development of acquired drug resistance. Because drug-tolerant cancer cells become cross-tolerant to other classes of cancer drugs, NLRP1 might be a suitable therapeutic target in drug-resistant melanoma, as well as in other cancers.
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Wang, Shao-An, Ming-Jer Young, Yi-Chang Wang, Shu-Hui Chen, Chia-Yu Liu, Yao-An Lo, Hung-Hsiang Jen, Kai-Cheng Hsu, and Jan-Jong Hung. "USP24 promotes drug resistance during cancer therapy." Cell Death & Differentiation 28, no. 9 (April 12, 2021): 2690–707. http://dx.doi.org/10.1038/s41418-021-00778-z.
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AbstractDrug resistance has remained an important issue in the treatment and prevention of various diseases, including cancer. Herein, we found that USP24 not only repressed DNA-damage repair (DDR) activity by decreasing Rad51 expression to cause the tumor genomic instability and cancer stemness, but also increased the levels of the ATP-binding cassette (ABC) transporters P-gp, ABCG2, and ezrin to enhance the pumping out of Taxol from cancer cells, thus resulted in drug resistance during cancer therapy. A novel USP24 inhibitor, NCI677397, was screened for specific inhibiting the catalytic activity of USP24. This inhibitor was identified to suppress drug resistance via decreasing genomic instability, cancer stemness, and the pumping out of drugs from cancer cells. Understanding the role and molecular mechanisms of USP24 in drug resistance will be beneficial for the future development of a novel USP24 inhibitor. Our studies provide a new insight of USP24 inhibitor for clinically implication of blocking drug resistance during chemotherapy.
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Yanase, Kae, Satomi Tsukahara, Sakiyo Asada, Etsuko Ishikawa, Yasuo Imai, and Yoshikazu Sugimoto. "Gefitinib reverses breast cancer resistance protein–mediated drug resistance." Molecular Cancer Therapeutics 3, no. 9 (September 1, 2004): 1119–25. http://dx.doi.org/10.1158/1535-7163.1119.3.9.
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Abstract Breast cancer resistance protein (BCRP) is an ATP binding cassette transporter that confers resistance to a series of anticancer agents such as 7-ethyl-10-hydroxycamptothecin (SN-38), topotecan, and mitoxantrone. In this study, we evaluated the possible interaction of gefitinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, with BCRP. BCRP-transduced human epidermoid carcinoma A431 (A431/BCRP) cells acquired cellular resistance to gefitinib, suggesting that BCRP could be one of the determinants of gefitinib sensitivity in a certain sort of cells. Next, the effect of gefitinib on BCRP-mediated drug resistance was examined. Gefitinib reversed SN-38 resistance in BCRP-transduced human myelogenous leukemia K562 (K562/BCRP) or BCRP-transduced murine lymphocytic leukemia P388 (P388/BCRP) cells but not in these parental cells. In addition, gefitinib sensitized human colon cancer HT-29 cells, which endogenously express BCRP, to SN-38. Gefitinib increased intracellular accumulation of topotecan in K562/BCRP cells and suppressed ATP-dependent transport of estrone 3-sulfate, a substrate of BCRP, in membrane vesicles from K562/BCRP cells. These results suggest that gefitinib may overcome BCRP-mediated drug resistance by inhibiting the pump function of BCRP. Furthermore, P388/BCRP-transplanted mice treated with combination of irinotecan and gefitinib survived significantly longer than those treated with irinotecan alone or gefitinib alone. In conclusion, gefitinib is shown to interact with BCRP. BCRP expression in a certain sort of cells is supposed to be one of the determinants of gefitinib sensitivity. Gefitinib inhibits the transporter function of BCRP and reverses BCRP-mediated drug resistance both in vitro and in vivo.
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Dean, Michael, Tito Fojo, and Susan Bates. "Tumour stem cells and drug resistance." Nature Reviews Cancer 5, no. 4 (April 2005): 275–84. http://dx.doi.org/10.1038/nrc1590.
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Fontana, Fabrizio, Emanuela Carollo, Genevieve E. Melling, and David R. F. Carter. "Extracellular Vesicles: Emerging Modulators of Cancer Drug Resistance." Cancers 13, no. 4 (February 11, 2021): 749. http://dx.doi.org/10.3390/cancers13040749.
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Extracellular vesicles (EVs) have recently emerged as crucial modulators of cancer drug resistance. Indeed, it has been shown that they can directly sequester anti-tumor drugs, decreasing their effective concentration at target sites. Moreover, they facilitate the horizontal transfer of specific bioactive cargoes able to regulate proliferative, apoptotic, and stemness programs in recipient cells, potentially conferring a resistant phenotype to drug-sensitive cancer cells. Finally, EVs can mediate the communication between the tumor and both stromal and immune cells within the microenvironment, promoting treatment escape. In this context, clarifying the EV-driven resistance mechanisms might improve not only tumor diagnosis and prognosis but also therapeutic outcomes. Detailed cellular and molecular events occurring during the development of EV-mediated cancer drug resistance are described in this review article.
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Maurya, Santosh K., G. G. H. A. Shadab, and Hifzur R. Siddique. "Chemosensitization of Therapy Resistant Tumors: Targeting Multiple Cell Signaling Pathways by Lupeol, A Pentacyclic Triterpene." Current Pharmaceutical Design 26, no. 4 (March 18, 2020): 455–65. http://dx.doi.org/10.2174/1381612826666200122122804.
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Background: The resistance of cancer cells to different therapies is one of the major stumbling blocks for successful cancer treatment. Various natural and pharmaceuticals drugs are unable to control drug-resistance cancer cell's growth. Also, chemotherapy and radiotherapy have several side effects and cannot apply to the patient in excess. In this context, chemosensitization to the therapy-resistant cells by non-toxic phytochemicals could be an excellent alternative to combat therapy-resistant cancers. Objective: To review the currently available literature on chemosensitization of therapy resistance cancers by Lupeol for clinically approved drugs through targeting different cell signaling pathways. Methods: We reviewed relevant published articles in PubMed and other search engines from 1999 to 2019 to write this manuscript. The key words used for the search were “Lupeol and Cancer”, “Lupeol and Chemosensitization”, “Lupeol and Cell Signaling Pathways”, “Cancer Stem Cells and Lupeol” etc. The published results on the chemosensitization of Lupeol were compared and discussed. Results: Lupeol chemosensitizes drug-resistant cancer cells for clinically approved drugs. Lupeol alone or in combination with approved drugs inhibits inflammation in different cancer cells through modulation of expression of IL-6, TNF-α, and IFN-γ. Lupeol, through altering the expression levels of BCL-2, BAX, Survivin, FAS, Caspases, and PI3K-AKT-mTOR signaling pathway, significantly induce cell deaths among therapy-resistant cells. Lupeol also modulates the molecules involved in cell cycle regulation such as Cyclins, CDKs, P53, P21, and PCNA in different cancer types. Conclusion: Lupeol chemosensitizes the therapy-resistant cancer cells for the treatment of various clinically approved drugs via modulating different signaling pathways responsible for chemoresistance cancer. Thus, Lupeol might be used as an adjuvant molecule along with clinically approved drugs to reduce the toxicity and increase the effectiveness.
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Naujokat, Cord, and Roman Steinhart. "Salinomycin as a Drug for Targeting Human Cancer Stem Cells." Journal of Biomedicine and Biotechnology 2012 (2012): 1–17. http://dx.doi.org/10.1155/2012/950658.
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Cancer stem cells (CSCs) represent a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of malignant cells that comprise a tumor. CSCs possess multiple intrinsic mechanisms of resistance to chemotherapeutic drugs, novel tumor-targeted drugs, and radiation therapy, allowing them to survive standard cancer therapies and to initiate tumor recurrence and metastasis. Various molecular complexes and pathways that confer resistance and survival of CSCs, including expression of ATP-binding cassette (ABC) drug transporters, activation of the Wnt/β-catenin, Hedgehog, Notch and PI3K/Akt/mTOR signaling pathways, and acquisition of epithelial-mesenchymal transition (EMT), have been identified recently. Salinomycin, a polyether ionophore antibiotic isolated fromStreptomyces albus, has been shown to kill CSCs in different types of human cancers, most likely by interfering with ABC drug transporters, the Wnt/β-catenin signaling pathway, and other CSC pathways. Promising results from preclinical trials in human xenograft mice and a few clinical pilote studies reveal that salinomycin is able to effectively eliminate CSCs and to induce partial clinical regression of heavily pretreated and therapy-resistant cancers. The ability of salinomycin to kill both CSCs and therapy-resistant cancer cells may define the compound as a novel and an effective anticancer drug.
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Li, Jing, Xiao Li, and Qie Guo. "Drug Resistance in Cancers: A Free Pass for Bullying." Cells 11, no. 21 (October 26, 2022): 3383. http://dx.doi.org/10.3390/cells11213383.
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The cancer burden continues to grow globally, and drug resistance remains a substantial challenge in cancer therapy. It is well established that cancerous cells with clonal dysplasia generate the same carcinogenic lesions. Tumor cells pass on genetic templates to subsequent generations in evolutionary terms and exhibit drug resistance simply by accumulating genetic alterations. However, recent evidence has implied that tumor cells accumulate genetic alterations by progressively adapting. As a result, intratumor heterogeneity (ITH) is generated due to genetically distinct subclonal populations of cells coexisting. The genetic adaptive mechanisms of action of ITH include activating “cellular plasticity”, through which tumor cells create a tumor-supportive microenvironment in which they can proliferate and cause increased damage. These highly plastic cells are located in the tumor microenvironment (TME) and undergo extreme changes to resist therapeutic drugs. Accordingly, the underlying mechanisms involved in drug resistance have been re-evaluated. Herein, we will reveal new themes emerging from initial studies of drug resistance and outline the findings regarding drug resistance from the perspective of the TME; the themes include exosomes, metabolic reprogramming, protein glycosylation and autophagy, and the relates studies aim to provide new targets and strategies for reversing drug resistance in cancers.
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Lee, Jae-Seon, Ho Lee, Hyonchol Jang, Sang Myung Woo, Jong Bae Park, Seon-Hyeong Lee, Joon Hee Kang, Hee Yeon Kim, Jaewhan Song, and Soo-Youl Kim. "Targeting Oxidative Phosphorylation Reverses Drug Resistance in Cancer Cells by Blocking Autophagy Recycling." Cells 9, no. 9 (September 1, 2020): 2013. http://dx.doi.org/10.3390/cells9092013.
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The greatest challenge in cancer therapy is posed by drug-resistant recurrence following treatment. Anticancer chemotherapy is largely focused on targeting the rapid proliferation and biosynthesis of cancer cells. This strategy has the potential to trigger autophagy, enabling cancer cell survival through the recycling of molecules and energy essential for biosynthesis, leading to drug resistance. Autophagy recycling contributes amino acids and ATP to restore mTOR complex 1 (mTORC1) activity, which leads to cell survival. However, autophagy with mTORC1 activation can be stalled by reducing the ATP level. We have previously shown that cytosolic NADH production supported by aldehyde dehydrogenase (ALDH) is critical for supplying ATP through oxidative phosphorylation (OxPhos) in cancer cell mitochondria. Inhibitors of the mitochondrial complex I of the OxPhos electron transfer chain and ALDH significantly reduce the ATP level selectively in cancer cells, terminating autophagy triggered by anticancer drug treatment. With the aim of overcoming drug resistance, we investigated combining the inhibition of mitochondrial complex I, using phenformin, and ALDH, using gossypol, with anticancer drug treatment. Here, we show that OxPhos targeting combined with anticancer drugs acts synergistically to enhance the anticancer effect in mouse xenograft models of various cancers, which suggests a potential therapeutic approach for drug-resistant cancer.
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Onishi, Yasuhiko, Yuki Eshita, Rui-Cheng Ji, Takashi Kobayashi, Masayasu Onishi, Masaaki Mizuno, Jun Yoshida, and Naoji Kubota. "Supermolecular drug challenge to overcome drug resistance in cancer cells." Drug Discovery Today 23, no. 8 (August 2018): 1556–63. http://dx.doi.org/10.1016/j.drudis.2018.05.037.
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Mancini, Rock, Amy E. Nielsen, Joseph D. Hantho, and Anthony J. Burt. "Drugging drug resistance with bystander-assisted immunotherapy." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 58.14. http://dx.doi.org/10.4049/jimmunol.200.supp.58.14.
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Abstract Acquired drug resistance is a longstanding challenge that reduces the efficacy of chemotherapeutic drugs. In contrast, the efficacies of modern immunotherapies do not directly correlate to the prevalence of chemo-resistant phenotypes. Here we improve upon this paradigm by targeting the action of immunotherapeutics to two general mechanisms of acquired drug resistance: irregular metabolism and drug efflux mediated by the ABC superfamily of transport proteins. In chemo-resistant prostate cancer cells, we demonstrate that these two mechanisms act in concert to selectively metabolize our newly developed class of enzyme-directed prodrug to the Toll-Like Receptor 7 immunotherapeutic Imiquimod. Following metabolism, liberated Imiquimod undergoes drug efflux to the extracellular space where it activates bystander immune cells in local proximity. In-vitro, we characterize this process of Bystander-Assisted ImmunoTherapy (BAIT) using an AT3B-1 chemo-resistant prostate cancer model with RAW-Blue and JAWSII reporter immune cell lines. Co-culture of AT3B-1 cancer cells with reporter immune cells results in immunogenicity mediated selectively by cancer cells. This results in enhanced NF-κB transcription, expression of cell surface markers, and secreted cytokines indicative of a cell-mediated immune response. Our prodrug is non-immunogenic with healthy cells alone and the enzyme-directing groups are stable for over 3 days in serum. Taken together, our results demonstrate that BAIT co-opts common mechanisms of drug resistance to elicit immunogenicity mediated by cancer cells themselves. We anticipate that BAIT will find use as a new mechanism of action that exploits drug resistant phenotypes to generate an immune response.
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Pulukuri, Anunay J., Anthony J. Burt, Larissa K. Opp, Colin M. McDowell, Maryam Davaritouchaee, Amy E. Nielsen, and Rock J. Mancini. "Acquired Drug Resistance Enhances Imidazoquinoline Efflux by P-Glycoprotein." Pharmaceuticals 14, no. 12 (December 10, 2021): 1292. http://dx.doi.org/10.3390/ph14121292.
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Multidrug-Resistant (MDR) cancers attenuate chemotherapeutic efficacy through drug efflux, a process that transports drugs from within a cell to the extracellular space via ABC (ATP-Binding Cassette) transporters, including P-glycoprotein 1 (P-gp or ABCB1/MDR1). Conversely, Toll-Like Receptor (TLR) agonist immunotherapies modulate activity of tumor-infiltrating immune cells in local proximity to cancer cells and could, therefore, benefit from the enhanced drug efflux in MDR cancers. However, the effect of acquired drug resistance on TLR agonist efflux is largely unknown. We begin to address this by investigating P-gp mediated efflux of TLR 7/8 agonists. First, we used functionalized liposomes to determine that imidazoquinoline TLR agonists Imiquimod, Resiquimod, and Gardiquimod are substrates for P-gp. Interestingly, the least potent imidazoquinoline (Imiquimod) was the best P-gp substrate. Next, we compared imidazoquinoline efflux in MDR cancer cell lines with enhanced P-gp expression relative to parent cancer cell lines. Using P-gp competitive substrates and inhibitors, we observed that imidazoquinoline efflux occurs through P-gp and, for Imiquimod, is enhanced as a consequence of acquired drug resistance. This suggests that enhancing efflux susceptibility could be an important consideration in the rational design of next generation immunotherapies that modulate activity of tumor-infiltrating immune cells.
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Visconti, Roberta, and Domenico Grieco. "Fighting tubulin-targeting anticancer drug toxicity and resistance." Endocrine-Related Cancer 24, no. 9 (September 2017): T107—T117. http://dx.doi.org/10.1530/erc-17-0120.
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Tubulin-targeting drugs, like taxanes and vinca alkaloids, are among the most effective anticancer therapeutics used in the clinic today. Specifically, anti-microtubule cancer drugs (AMCDs) have proven to be effective in the treatment of castration-resistant prostate cancer and triple-negative breast cancer. AMCDs, however, have limiting toxicities that include neutropenia and neurotoxicity, and, in addition, tumor cells can become resistant to the drugs after long-term use. Co-targeting mitotic progression/slippage with inhibition of the protein kinases WEE1 and MYT1 that regulate CDK1 kinase activity may improve AMCD efficacy, reducing the acquisition of resistance by the tumor and side effects from the drug and/or its vehicle. Other possible treatments that improve outcomes in the clinic for these two drug-resistant cancers, including new formulations of the AMCDs and pursuing different molecular targets, will be discussed.
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Saputra, Elysia, and Lisa Tucker-Kellogg. "Abstract B026: Simulations of cancer evolution predict relative benefits of synergistic and non-synergistic drug combinations for combating different landscapes of drug-resistance." Cancer Research 82, no. 10_Supplement (May 15, 2022): B026. http://dx.doi.org/10.1158/1538-7445.evodyn22-b026.
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Abstract Cancer therapies often have short duration of success due to the development of drug-resistance, which motivates research into anti-evolutionary therapies. A popular strategy is to combine two drugs, particularly if they have synergistic (greater-than-additive) efficacy. However, therapies that cause synergistic suppression of drug-sensitive cells will also suffer from synergistic release of drug-resistant cells, when drug-resistance arises. Not yet understood is the impact of partial drug-resistance and semi-resistant phenotypes on the speed of clonal expansion under combination therapy. In this work, we perform computational modeling to compare the growth rates of heterogeneous populations of cells, when drug-resistance is a binary (all-or-nothing) phenotype, versus when it is a spectrum of partially-sensitive phenotypes. We ask whether the type and granularity of drug-resistance levels in the drug-resistance landscape affects the relative outcome of using synergistic versus non-synergistic drug combinations. We observe that if drug-resistance can develop via rapid, “plastic” phenotypic transitions, then synergistic drugs provide long-lasting suppression of resistance than additive drugs (when dosed to have equal initial efficacy). Conversely, if drug-resistance develops via slow acquisition of phenotypic changes (e.g., requiring multiple genomic lesions), then synergistic drugs promote faster evolution of drug-resistance than additive drugs. When studying how synergism affects evolution, we found that cells escaping a synergistic treatment would be more likely to develop “asymmetric resistance” toward one drug (with greater sensitivity toward the other drug). In contrast, cells escaping antagonistic treatments would be more likely to develop symmetric resistance (equal levels of resistance) toward both drugs. Our findings suggest that after a synergistic treatment, a post-relapse tumor would be more likely to retain sensitivity to one of the drugs used, compared with equivalent relapse after non-synergistic combination treatment. Thus, theoretical modeling can provide testable predictions that complement the hypotheses arising from experiments. Citation Format: Elysia Saputra, Lisa Tucker-Kellogg. Simulations of cancer evolution predict relative benefits of synergistic and non-synergistic drug combinations for combating different landscapes of drug-resistance [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B026.
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Beeraka, Narasimha M., Shalini H. Doreswamy, Surya P. Sadhu, Asha Srinivasan, Rajeswara Rao Pragada, SubbaRao V. Madhunapantula, and Gjumrakch Aliev. "The Role of Exosomes in Stemness and Neurodegenerative Diseases—Chemoresistant-Cancer Therapeutics and Phytochemicals." International Journal of Molecular Sciences 21, no. 18 (September 17, 2020): 6818. http://dx.doi.org/10.3390/ijms21186818.
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Exosomes exhibit a wide range of biological properties and functions in the living organisms. They are nanometric vehicles and used for delivering drugs, as they are biocompatible and minimally immunogenic. Exosomal secretions derived from cancer cells contribute to metastasis, immortality, angiogenesis, tissue invasion, stemness and chemo/radio-resistance. Exosome-derived microRNAs (miRNAs) and long non-coding RNAs (lnc RNAs) are involved in the pathophysiology of cancers and neurodegenerative diseases. For instance, exosomes derived from mesenchymal stromal cells, astrocytes, macrophages, and acute myeloid leukemia (AML) cells are involved in the cancer progression and stemness as they induce chemotherapeutic drug resistance in several cancer cells. This review covered the recent research advances in understanding the role of exosomes in cancer progression, metastasis, angiogenesis, stemness and drug resistance by illustrating the modulatory effects of exosomal cargo (ex. miRNA, lncRNAs, etc.) on cell signaling pathways involved in cancer progression and cancer stem cell growth and development. Recent reports have implicated exosomes even in the treatment of several cancers. For instance, exosomes-loaded with novel anti-cancer drugs such as phytochemicals, tumor-targeting proteins, anticancer peptides, nucleic acids are known to interfere with drug resistance pathways in several cancer cell lines. In addition, this review depicted the need to develop exosome-based novel diagnostic biomarkers for early detection of cancers and neurodegenerative disease. Furthermore, the role of exosomes in stroke and oxidative stress-mediated neurodegenerative diseases including Alzheimer’s disease (AD), and Parkinson’s disease (PD) is also discussed in this article.
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Soekmadji, Carolina, and Colleen C. Nelson. "The Emerging Role of Extracellular Vesicle-Mediated Drug Resistance in Cancers: Implications in Advanced Prostate Cancer." BioMed Research International 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/454837.
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Emerging evidence has shown that the extracellular vesicles (EVs) regulate various biological processes and can control cell proliferation and survival, as well as being involved in normal cell development and diseases such as cancers. In cancer treatment, development of acquired drug resistance phenotype is a serious issue. Recently it has been shown that the presence of multidrug resistance proteins such as Pgp-1 and enrichment of the lipid ceramide in EVs could have a role in mediating drug resistance. EVs could also mediate multidrug resistance through uptake of drugs in vesicles and thus limit the bioavailability of drugs to treat cancer cells. In this review, we discussed the emerging evidence of the role EVs play in mediating drug resistance in cancers and in particular the role of EVs mediating drug resistance in advanced prostate cancer. The role of EV-associated multidrug resistance proteins, miRNA, mRNA, and lipid as well as the potential interaction(s) among these factors was probed. Lastly, we provide an overview of the current available treatments for advanced prostate cancer, considering where EVs may mediate the development of resistance against these drugs.
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Kumar, Uttom, Anastasia Ardasheva, Zimam Mahmud, R. Charles Coombes, and Ernesto Yagüe. "FOXA1 is a determinant of drug resistance in breast cancer cells." Breast Cancer Research and Treatment 186, no. 2 (January 8, 2021): 317–26. http://dx.doi.org/10.1007/s10549-020-06068-5.
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Abstract Purpose Breast cancer is one of the most commonly diagnosed cancers in women. Five subtypes of breast cancer differ in their genetic expression profiles and carry different prognostic values, with no treatments available for some types, such as triple-negative, due to the absence of genetic signatures that could otherwise be targeted by molecular therapies. Although endocrine treatments are largely successful for estrogen receptor (ER)-positive cancers, a significant proportion of patients with metastatic tumors fail to respond and acquire resistance to therapy. FOXA1 overexpression mediates endocrine therapy resistance in ER-positive breast cancer, although the regulation of chemotherapy response by FOXA1 has not been addressed previously. FOXA1, together with EP300 and RUNX1, regulates the expression of E-cadherin, and is expressed in luminal, but absent in triple-negative and basal-like breast cancers. We have previously determined that EP300 regulates drug resistance and tumor initiation capabilities in breast cancer cells. Methods Here we describe the generation of breast cancer cell models in which FOXA1 expression has been modulated either by expression of hairpins targeting FOXA1 mRNA or overexpression plasmids. Results Upon FOXA1 knockdown in luminal MCF-7 and T47D cells, we found an increase in doxorubicin and paclitaxel sensitivity as well as a decrease in anchorage independence. Conversely, upregulation of FOXA1 in basal-like MDA-MB-231 cells led to an increase in drug resistance and anchorage independence. Conclusion Together, these data suggest that FOXA1 plays a role in making tumors more aggressive.
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Yoo, Hee-Chan, and Jung-Min Han. "Amino Acid Metabolism in Cancer Drug Resistance." Cells 11, no. 1 (January 2, 2022): 140. http://dx.doi.org/10.3390/cells11010140.
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Despite the numerous investigations on resistance mechanisms, drug resistance in cancer therapies still limits favorable outcomes in cancer patients. The complexities of the inherent characteristics of tumors, such as tumor heterogeneity and the complicated interaction within the tumor microenvironment, still hinder efforts to overcome drug resistance in cancer cells, requiring innovative approaches. In this review, we describe recent studies offering evidence for the essential roles of amino acid metabolism in driving drug resistance in cancer cells. Amino acids support cancer cells in counteracting therapies by maintaining redox homeostasis, sustaining biosynthetic processes, regulating epigenetic modification, and providing metabolic intermediates for energy generation. In addition, amino acid metabolism impacts anticancer immune responses, creating an immunosuppressive or immunoeffective microenvironment. A comprehensive understanding of amino acid metabolism as it relates to therapeutic resistance mechanisms will improve anticancer therapeutic strategies.
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Li, Rui, Chengyong Dong, Keqiu Jiang, Rui Sun, Yang Zhou, Zeli Yin, Jiaxin Lv, Junlin Zhang, Qi Wang, and Liming Wang. "Rab27B enhances drug resistance in hepatocellular carcinoma by promoting exosome-mediated drug efflux." Carcinogenesis 41, no. 11 (May 11, 2020): 1583–91. http://dx.doi.org/10.1093/carcin/bgaa029.
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Abstract Liver cancer is a major threat to human life and health, and chemotherapy has been the standard non-surgical treatment for liver cancer. However, the emergence of drug resistance of liver cancer cells has hindered the therapeutic effect of chemical drugs. The discovery of exosomes has provided new insights into the mechanisms underlying tumour cell resistance. In this study, we aimed to determine the proteins associated with drug resistance in tumour cells and to elucidate the underlying mechanisms. We found that Rab27B expression in drug (5-fluorouracil, 5Fu)-resistant Bel7402 (Bel/5Fu) cells increased significantly compared with that in drug-sensitive Bel7402 cells. In addition, Bel/5Fu cells secreted more exosomes under 5Fu stimulation. The number of exosomes secreted by Bel/5Fu cells significantly reduced after knocking down Rab27B, and the cellular concentration of 5Fu increased, enhancing its therapeutic effect. We also found that the administration of classical drug efflux pump (P-glycoprotein, P-gp) inhibitors together with knockdown of Rab27B further improved the therapeutic effects of chemotherapy drugs. In conclusion, our findings suggest that Rab27B could be a new therapeutic target in liver cancer.
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Hanikoglu, Aysegul, Hakan Ozben, Ferhat Hanikoglu, and Tomris Ozben. "Hybrid Compounds & Oxidative Stress Induced Apoptosis in Cancer Therapy." Current Medicinal Chemistry 27, no. 13 (April 24, 2020): 2118–32. http://dx.doi.org/10.2174/0929867325666180719145819.
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: Elevated Reactive Oxygen Species (ROS) generated by the conventional cancer therapies and the endogenous production of ROS have been observed in various types of cancers. In contrast to the harmful effects of oxidative stress in different pathologies other than cancer, ROS can speed anti-tumorigenic signaling and cause apoptosis of tumor cells via oxidative stress as demonstrated in several studies. The primary actions of antioxidants in cells are to provide a redox balance between reduction-oxidation reactions. Antioxidants in tumor cells can scavenge excess ROS, causing resistance to ROS induced apoptosis. Various chemotherapeutic drugs, in their clinical use, have evoked drug resistance and serious side effects. Consequently, drugs having single-targets are not able to provide an effective cancer therapy. Recently, developed hybrid anticancer drugs promise great therapeutic advantages due to their capacity to overcome the limitations encountered with conventional chemotherapeutic agents. Hybrid compounds have advantages in comparison to the single cancer drugs which have usually low solubility, adverse side effects, and drug resistance. This review addresses two important treatments strategies in cancer therapy: oxidative stress induced apoptosis and hybrid anticancer drugs.
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Holčáková, Jitka, Marta Nekulová, Paulina Orzol, and Bořivoj Vojtěšek. "Mechanisms of Drug Resistance and Cancer Stem Cells." Klinicka onkologie 27, Suppl 1 (June 15, 2014): S34—S41. http://dx.doi.org/10.14735/amko20141s34.
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Dean, Michael. "ABC Transporters, Drug Resistance, and Cancer Stem Cells." Journal of Mammary Gland Biology and Neoplasia 14, no. 1 (February 18, 2009): 3–9. http://dx.doi.org/10.1007/s10911-009-9109-9.
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Kamal, Mohamed, Ebtesam H. O. Nafie, Shimaa Elsers, Salma Alanwar, Rawayeh Ibrahim, Fatma Farag, Mohamed Mlees, et al. "Ethnicity influences breast cancer stem cells' drug resistance." Breast Journal 24, no. 4 (March 2, 2018): 701–3. http://dx.doi.org/10.1111/tbj.13021.
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Rosa, Roberta, Valentina D’Amato, Sabino De Placido, and Roberto Bianco. "Approaches for targeting cancer stem cells drug resistance." Expert Opinion on Drug Discovery 11, no. 12 (October 14, 2016): 1201–12. http://dx.doi.org/10.1080/17460441.2016.1243525.
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Wang, Shuai, Wujun Chen, Hualong Yu, Zhengming Song, Qian Li, Xin Shen, Yudong Wu, Lei Zhu, Qingxia Ma, and Dongming Xing. "lncRNA ROR Promotes Gastric Cancer Drug Resistance." Cancer Control 27, no. 1 (January 1, 2020): 107327482090469. http://dx.doi.org/10.1177/1073274820904694.
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Objective: Gastric cancer is one of the most common malignant tumors worldwide, and for resectable tumors, the most effective treatment is surgery with chemotherapy in neoadjuvant or adjuvant setting. However, the majority of patients fail to achieve the ideal initial response and/or develop resistance to chemotherapy. It was reported that long noncoding RNA regulator of reprogramming (ROR) is highly associated with the progression of gastric cancer. However, the role ROR in multidrug resistance (MDR) remains unclear. Methods: The messenger RNA levels of 63 specimens of patients with gastric cancer were determined by real-time polymerase chain reaction analysis and were correlated with drug resistance and survival of patients. To determine the cellular functions of ROR, we generated gastric cancer MDR cells. The effect of ROR depletion on multidrug resistance-associated protein 1 (MRP1) expression and cell apoptosis were examined by immunoblotting analyses, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and flow cytometry. Results: We found that ROR expression levels are positively associated with increased MDR and poor prognosis of patients with gastric cancer. Regulator of reprogramming expression is increased in gastric cancer cells resistant to adriamycin (ADR) and vincristine (VCR). Depletion of ROR reduced MRP1 expression and increased apoptosis of drug-resistant gastric cancer cells in response to ADR and VCR treatment. Conclusions: We demonstrated that ROR expression promotes MRP1 expression and MDR of gastric cancer cells and is correlated with increased MDR and poor prognosis of patients with gastric cancer. Our finding highlighted the potential of targeting ROR to improve the efficacy of chemotherapy.
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Karwicka, Ewa. "Role of Glutathione in the Multidrug Resistance in Cancer." Advances in Cell Biology 2, no. 3 (April 1, 2010): 105–24. http://dx.doi.org/10.2478/v10052-010-0006-6.
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SummaryMultidrug resistance is the main problem in anticancer therapy. Cancer cells use many defense strategies in order to survive chemotherapy. Among known multidrug resistance mechanisms the most important are: drug detoxification inside the cell using II phase detoxifying enzymes and active transport of the drug to the extracellular environment. Cancer cells may be also less sensitive to proapoptotic signals and have different intracellular drug distribution, which makes them more resistant to anticancer drugs. Role of glutathione in multidrug resistance is the object of interest of many scientists, however, defining it’s function in these processes still remains a challenge. In this paper, properties of glutathione and it’s role in multidrug resistance in cancer cells were described.
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Kozovska, Zuzana, Veronika Gabrisova, and Lucia Kucerova. "Colon cancer: Cancer stem cells markers, drug resistance and treatment." Biomedicine & Pharmacotherapy 68, no. 8 (October 2014): 911–16. http://dx.doi.org/10.1016/j.biopha.2014.10.019.
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Safa, Ahmad R. "Drug and apoptosis resistance in cancer stem cells (CSCs): A puzzle with many pieces." Cancer Drug Resistance 5, no. 4 (2022): 850–72. http://dx.doi.org/10.20517/cdr.2022.20.
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Resistance to anti-cancer agents and apoptosis results in cancer relapse and is associated with cancer mortality. Substantial data have provided convincing evidence establishing that human cancers emerge from cancer stem cells (CSCs), which display self-renewal and are resistant to anti-cancer drugs, radiation, and apoptosis, and express enhanced epithelial to mesenchymal (EMT) progression. CSCs represent a heterogeneous tumor cell population and lack specific cellular targets, which makes it a great challenge to target and eradicate them. Similarly, their close relationship with the tumor microenvironment (TME) creates greater complexity in developing novel treatment strategies targeting CSCs. Several mechanisms participate in the drug and apoptosis resistance phenotype in CSCs in various cancers. These include enhanced expression of ATP-binding cassette (ABC) membrane transporters, activation of various cytoprotective and survival signaling pathways, dysregulation of stemness signaling pathways, aberrant DNA repair mechanisms, increased quiescence, autophagy, increased immune evasion, deficiency of mitochondrial-mediated apoptosis, upregulation of anti-apoptotic proteins including c-FLIP (cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein), Bcl-2 family members, inhibitors of apoptosis proteins (IAPs), and PI3K/AKT signaling. Studying such mechanisms not only provides mechanistic insights into these cells that are unresponsive to drugs, but may lead to the development of targeted and effective therapeutics to eradicate CSCs. Several studies have identified promising strategies to target CSCs. These emerging strategies may help target CSC-associated drug resistance and metastasis in clinical settings. This article will review the CSCs drug and apoptosis resistance mechanisms and how to target CSCs.
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Lim, Jin Hong, Keunwan Park, Kyung Hwa Choi, Chan Wung Kim, Jae Ha Lee, Raymond Weicker, Cheol-Ho Pan, Seok-Mo Kim, and Ki Cheong Park. "Drug Discovery Using Evolutionary Similarities in Chemical Binding to Inhibit Patient-Derived Hepatocellular Carcinoma." International Journal of Molecular Sciences 23, no. 14 (July 19, 2022): 7971. http://dx.doi.org/10.3390/ijms23147971.
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Drug resistance causes therapeutic failure in refractory cancer. Cancer drug resistance stems from various factors, such as patient heterogeneity and genetic alterations in somatic cancer cells, including those from identical tissues. Generally, resistance is intrinsic for cancers; however, cancer resistance becomes common owing to an increased drug treatment. Unfortunately, overcoming this issue is not yet possible. The present study aimed to evaluate a clinical approach using candidate compounds 19 and 23, which are sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) inhibitors, discovered using the evolutionary chemical binding similarity method. mRNA sequencing indicated SERCA as the dominant marker of patient-derived anti-cancer drug-resistant hepatocellular carcinoma (HCC), but not of patient-derived anti-cancer drug-sensitive HCC. Candidate compounds 19 and 23 led to significant tumor shrinkage in a tumor xenograft model of anti-cancer drug-resistant patient-derived HCC cells. Our results might be clinically significant for the development of novel combinatorial strategies that selectively and efficiently target highly malignant cells such as drug-resistant and cancer stem-like cells.
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Castellón, Enrique, and Héctor Contreras. "Cancer Stem Cells in Human Prostate Cancer. Role in Drug Resistance and Metastasis." International Journal of Medical and Surgical Sciences 2, no. 4 (October 26, 2018): 711–22. http://dx.doi.org/10.32457/ijmss.2015.045.
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Prostate cancer is one of the most important causes of oncologic death in men, and Chile has also reached that level. Prostate cancer mortality is mostly associated with metastatic disease where the cancer is usually resistant to available treatments, particularly hormone- therapy and chemotherapy. It has been suggested that the existence of cancer stem cells could account for the metastatic capacity and treatment resistance in most cancers. Recently, cells with stem characteristics have been identified in established cell lines and animal models of prostate cancer. We have isolated and characterized this kind of cells from patient tumors. This finding opens the possibility to manipulate them as potential therapeutic targets.
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Ambjørner, Sophie E. B., Michael Wiese, Sebastian Christoph Köhler, Joen Svindt, Xamuel Loft Lund, Michael Gajhede, Lasse Saaby, et al. "The Pyrazolo[3,4-d]pyrimidine Derivative, SCO-201, Reverses Multidrug Resistance Mediated by ABCG2/BCRP." Cells 9, no. 3 (March 4, 2020): 613. http://dx.doi.org/10.3390/cells9030613.
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ATP-binding cassette (ABC) transporters, such as breast cancer resistance protein (BCRP), are key players in resistance to multiple anti-cancer drugs, leading to cancer treatment failure and cancer-related death. Currently, there are no clinically approved drugs for reversal of cancer drug resistance caused by ABC transporters. This study investigated if a novel drug candidate, SCO-201, could inhibit BCRP and reverse BCRP-mediated drug resistance. We applied in vitro cell viability assays in SN-38 (7-Ethyl-10-hydroxycamptothecin)-resistant colon cancer cells and in non-cancer cells with ectopic expression of BCRP. SCO-201 reversed resistance to SN-38 (active metabolite of irinotecan) in both model systems. Dye efflux assays, bidirectional transport assays, and ATPase assays demonstrated that SCO-201 inhibits BCRP. In silico interaction analyses supported the ATPase assay data and suggest that SCO-201 competes with SN-38 for the BCRP drug-binding site. To analyze for inhibition of other transporters or cytochrome P450 (CYP) enzymes, we performed enzyme and transporter assays by in vitro drug metabolism and pharmacokinetics studies, which demonstrated that SCO-201 selectively inhibited BCRP and neither inhibited nor induced CYPs. We conclude that SCO-201 is a specific, potent, and potentially non-toxic drug candidate for the reversal of BCRP-mediated resistance in cancer cells.
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BeLow, McKenna, and Clodia Osipo. "Notch Signaling in Breast Cancer: A Role in Drug Resistance." Cells 9, no. 10 (September 29, 2020): 2204. http://dx.doi.org/10.3390/cells9102204.
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Breast cancer is a heterogeneous disease that can be subdivided into unique molecular subtypes based on protein expression of the Estrogen Receptor, Progesterone Receptor, and/or the Human Epidermal Growth Factor Receptor 2. Therapeutic approaches are designed to inhibit these overexpressed receptors either by endocrine therapy, targeted therapies, or combinations with cytotoxic chemotherapy. However, a significant percentage of breast cancers are inherently resistant or acquire resistance to therapies, and mechanisms that promote resistance remain poorly understood. Notch signaling is an evolutionarily conserved signaling pathway that regulates cell fate, including survival and self-renewal of stem cells, proliferation, or differentiation. Deregulation of Notch signaling promotes resistance to targeted or cytotoxic therapies by enriching of a small population of resistant cells, referred to as breast cancer stem cells, within the bulk tumor; enhancing stem-like features during the process of de-differentiation of tumor cells; or promoting epithelial to mesenchymal transition. Preclinical studies have shown that targeting the Notch pathway can prevent or reverse resistance through reduction or elimination of breast cancer stem cells. However, Notch inhibitors have yet to be clinically approved for the treatment of breast cancer, mainly due to dose-limiting gastrointestinal toxicity. In this review, we discuss potential mechanisms of Notch-mediated resistance in breast cancer cells and breast cancer stem cells, and various methods of targeting Notch through γ-secretase inhibitors, Notch signaling biologics, or transcriptional inhibitors. We also discuss future plans for identification of novel Notch-targeted therapies, in order to reduce toxicity and improve outcomes for women with resistant breast cancer.
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Ceballos, María Paula, Juan Pablo Rigalli, Lucila Inés Ceré, Mariana Semeniuk, Viviana Alicia Catania, and María Laura Ruiz. "ABC Transporters: Regulation and Association with Multidrug Resistance in Hepatocellular Carcinoma and Colorectal Carcinoma." Current Medicinal Chemistry 26, no. 7 (May 14, 2019): 1224–50. http://dx.doi.org/10.2174/0929867325666180105103637.
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:For most cancers, the treatment of choice is still chemotherapy despite its severe adverse effects, systemic toxicity and limited efficacy due to the development of multidrug resistance (MDR). MDR leads to chemotherapy failure generally associated with a decrease in drug concentration inside cancer cells, frequently due to the overexpression of ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs), and breast cancer resistance protein (BCRP/ABCG2), which limits the efficacy of chemotherapeutic drugs. The aim of this review is to compile information about transcriptional and post-transcriptional regulation of ABC transporters and discuss their role in mediating MDR in cancer cells.:This review also focuses on drug resistance by ABC efflux transporters in cancer cells, particularly hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) cells. Some aspects of the chemotherapy failure and future directions to overcome this problem are also discussed.
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To, Kenneth K. W., and William C. S. Cho. "Flavonoids Overcome Drug Resistance to Cancer Chemotherapy by Epigenetically Modulating Multiple Mechanisms." Current Cancer Drug Targets 21, no. 4 (May 27, 2021): 289–305. http://dx.doi.org/10.2174/1568009621666210203111220.
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Drug resistance is the major reason accounting for the treatment failure in cancer chemotherapy. Dysregulation of the epigenetic machineries is known to induce chemoresistance. It was reported that numerous genes encoding the key mediators in cancer proliferation, apoptosis, DNA repair, and drug efflux are dysregulated in resistant cancer cells by aberrant DNA methylation. The imbalance of various enzymes catalyzing histone post-translational modifications is also known to alter chromatin configuration and regulate multiple drug resistance genes. Alteration in miRNA signature in cancer cells also gives rise to chemoresistance. Flavonoids are a large group of naturally occurring polyphenolic compounds ubiquitously found in plants, fruits, vegetables and traditional herbs. There has been increasing research interest in the health-promoting effects of flavonoids. Flavonoids were shown to directly kill or re-sensitize resistant cancer cells to conventional anticancer drugs by epigenetic mechanisms. In this review, we summarize the current findings of the circumvention of drug resistance by flavonoids through correcting the aberrant epigenetic regulation of multiple resistance mechanisms. More investigations including the evaluation of synergistic anticancer activity, dosing sequence effect, toxicity in normal cells, and animal studies, are warranted to establish the full potential of the combination of flavonoids with conventional chemotherapeutic drugs in the treatment of cancer with drug resistance.
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Kreutzer, David, Christoph Ritter, and Andreas Hilgeroth. "Novel Nonsymmetrical 1,4-Dihydropyridines as Inhibitors of Nonsymmetrical MRP-Efflux Pumps for Anticancer Therapy." Pharmaceuticals 13, no. 7 (July 9, 2020): 146. http://dx.doi.org/10.3390/ph13070146.
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Cancer is a strong global burden with increasing numbers of diseases and ongoing anticancer drug resistance. The number of structurally novel anticancer drugs is strongly limited. They cause high costs for the social health systems. Most critical so-called multidrug resistances (MDR) are caused by transmembrane efflux pumps that transport drugs with various structures out of the cancer cells. Multidrug resistance proteins (MRPs) type 1 and 2 are found overexpressed in various kinds of cancer. There is a strong need for inhibitors of those efflux pumps. We developed novel nonsymmetrical 1,4-dihydropyridines as novel inhibitors of cancer relevant MRP types 1 and 2. The structure-dependent activities of the differently substituted derivatives were evaluated in cellular assays of respective cancer cells and are discussed. Promising candidates were identified. One candidate was demonstrated to resensitize a cisplatin resistant cancer cell line and thus to overcome the anticancer drug resistance.
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Khan, Muhammad Muzamil, and Vladimir P. Torchilin. "Recent Trends in Nanomedicine-Based Strategies to Overcome Multidrug Resistance in Tumors." Cancers 14, no. 17 (August 26, 2022): 4123. http://dx.doi.org/10.3390/cancers14174123.
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Cancer is the leading cause of economic and health burden worldwide. The commonly used approaches for the treatment of cancer are chemotherapy, radiotherapy, and surgery. Chemotherapy frequently results in undesirable side effects, and cancer cells may develop resistance. Combating drug resistance is a challenging task in cancer treatment. Drug resistance may be intrinsic or acquired and can be due to genetic factors, growth factors, the increased efflux of drugs, DNA repair, and the metabolism of xenobiotics. The strategies used to combat drug resistance include the nanomedicine-based targeted delivery of drugs and genes using different nanocarriers such as gold nanoparticles, peptide-modified nanoparticles, as well as biomimetic and responsive nanoparticles that help to deliver payload at targeted tumor sites and overcome resistance. Gene therapy in combination with chemotherapy aids in this respect. siRNA and miRNA alone or in combination with chemotherapy improve therapeutic response in tumor cells. Some natural substances, such as curcumin, quercetin, tocotrienol, parthenolide, naringin, and cyclosporin-A are also helpful in combating the drug resistance of cancer cells. This manuscript summarizes the mechanism of drug resistance and nanoparticle-based strategies used to combat it.
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Wardhani, Bantari Wisynu Kusuma, Meidi Utami Puteri, Yukihide Watanabe, Melva Louisa, Rianto Setiabudy, and Mitsuyasu Kato. "Decreased sensitivity of several anticancer drugs in TMEPAI knockout triple-negative breast cancer cells." Medical Journal of Indonesia 28, no. 2 (August 9, 2019): 110–5. http://dx.doi.org/10.13181/mji.v28i2.2687.
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BACKGROUND Transmembrane prostate androgen-induced protein (TMEPAI) was reported to be highly amplified in the majority of patients with triple-negative breast cancer (TNBC). TMEPAI is related to poorer prognosis, limited treatment options, and prone to drug resistance compared with other proteins. One of the established markers to determine cancer resistance to drugs is the increased expression levels of drug efflux transporters. However, the role of TMEPAI in cancer resistance to drugs has not been elucidated. This study was aimed to investigate whether TMEPAI participates in cancer resistance to drugs by regulating drug efflux transporters.
METHODS TMEPAI knockout (KO) cells were previously developed from a TNBC cell line, Hs578T (wild-type/WT), using a CRISPR-Cas9 system. The expression levels of drug efflux transporters were determined in Hs578T-KO and Hs578-WT by quantitative reverse transcriptase polymerase chain reaction. Cytotoxic concentration 50% (CC50) of several anticancer drugs (doxorubicin, cisplatin, and paclitaxel) were determined in the two cell lines via 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay.
RESULTS The results showed that the mRNA expression of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) was significantly increased in Hs578T-KO compared with that in Hs578T-WT cells. CC50 of several anticancer drugs investigated (doxorubicin, paclitaxel, and cisplatin) in Hs578T-KO cells was higher than that in Hs678-WT.
CONCLUSIONS TMEPAI participated in the regulation of mRNA expression levels in drug efflux transporters (P-gp, BCRP, and multidrug resistance-associated protein 1). Further studies are necessary to confirm whether this finding might be dependent on the development of cancer cell sensitivity to anticancer agents.
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Zeng, Renya, and Jixin Dong. "The Hippo Signaling Pathway in Drug Resistance in Cancer." Cancers 13, no. 2 (January 16, 2021): 318. http://dx.doi.org/10.3390/cancers13020318.
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Chemotherapy represents one of the most efficacious strategies to treat cancer patients, bringing advantageous changes at least temporarily even to those patients with incurable malignancies. However, most patients respond poorly after a certain number of cycles of treatment due to the development of drug resistance. Resistance to drugs administrated to cancer patients greatly limits the benefits that patients can achieve and continues to be a severe clinical difficulty. Among the mechanisms which have been uncovered to mediate anti-cancer drug resistance, the Hippo signaling pathway is gaining increasing attention due to the remarkable oncogenic activities of its components (for example, YAP and TAZ) and their druggable properties. This review will highlight current understanding of how the Hippo signaling pathway regulates anti-cancer drug resistance in tumor cells, and currently available pharmacological interventions targeting the Hippo pathway to eradicate malignant cells and potentially treat cancer patients.