Cancer stem cells cscs, also known as tumorinitiating cells tics, are suggested to be responsible for drug resistance and cancer relapse due in part to their ability to selfrenew themselves and differentiate into heterogeneous lineages of cancer cells. Rapidly proliferating normal cells are more sensitive to cytotoxic drugs. Explaining the high mutation rates of cancer cells to drug and multidrug resistance by chromosome reassortments that are catalyzed by aneuploidy. To study the detailed mechanism, we established drugresistant cells from a crc cell line and performed a microarray analysis.
Elevation of gst expression in cancer cells enhances detoxification of the anticancer drugs, which results in less efficient cytotoxic damage of the cells 12. In addition to known drug targets and resistance mechanisms, this study revealed novel insights into drug mechanisms of action, including cellular transporters, drug target. The mechanism may work by inducing the apoptosis of ovarian cancer. Drug resistance is an important problem in the treatment of patients with cancer. Various cancer chemopreventive phytochemicals can sensitize chemoresistant and radioresistant cancer cells. The moonshot drug resistance and sensitivity network, was established to develop innovative strategies and study mechanisms of tumor resistance or sensitivity to anticancer therapies that ultimately inform precision medicine clinical trials that can overcome drug resistance to anti cancer agents.
Drug resistance in tumor cells hinders the development of effective cancer therapies and limits the efficacy of both traditional chemotherapeutic agents for example, taxanes and platinum compounds and more recently discovered drugs that target specific molecules for example, egf receptor egfr and cabl kinase inhibitors. Three published transcriptome microarray data were downloaded. The sensitivity of these paired cell lines is usually determined by exposing them to a range of drug concentrations and then assessing cell viability. The overexpression of cd44 in cancer cells was strongly linked to therapeutic drug resistance 7.
In the chemotherapy, by following the administration of a certain drug, a large number of patient tumor cells become resistant to the drug. One such example is resistance to platelet inhibitors 43, where overexpression of the drug target is one of the mechanisms that lead to failure of treatment. An overview genevieve housman 1, shannon byler 2, sarah heerboth 2, karolina lapinska 2. Pdf overcoming multidrug resistance in cancer stem cells. In the present study, we explored the role of dicer in cisplatin resistant lung cancer cells a549 ddp and further to investigate the molecular mechanism of dicer in a549ddp cancer cells. The cancer cells may learn how to repair the dna breaks caused by some anti cancer drugs.
Cancer cells send signals boosting survival and drug. In vitro development of chemotherapy and targeted therapy. In the present study, we compared cocultured admsc and human epidermal receptor 2. Selenadiazole derivatives antagonize hyperglycemiainduced. Hyperglycemia is an important factor for chemoresistance of breast cancer patients with diabetes. It would give new clues and be used as a theoretical reference for the drug resistance of lung cancer. Age, diet, and stomach dis ease are the potential factors determining the development and progression of gastric cancer 1. Lorlatinib is a thirdgeneration anaplastic lymphoma kinase alk tyrosine kinase inhibitor with proven efficacy in patients with alkrearranged lung cancer previously treated with first and secondgeneration alk inhibitors. Drug resistance is a serious impediment to the treatment of cancer. Cancer cells require a high amount of glucose in comparison with surrounding tissues 2050 times 6,7, and this glucose is converted into lactate, even in high oxygen concentrations. Nih funding opportunities and notices in the nih guide for grants and contracts.
Cancer lipid metabolism confers antiangiogenic drug. However, the mechanisms involved remain poorly understood. Recent advances in apoptosis, mitochondria and drug. This has spurred a massive effort by the cancer research community to identify mechanisms used by cancer cells to evade treatment. Cancer cells send signals boosting survival and drug resistance in other cancer cells. In fact, drug resistance is observed in the clinic not only in cancer and pathogendriven diseases, but also in other cases. Despite the remarkable clinical efficacy demonstrated by molecularly targeted cancer therapeutics, the benefits are typically temporary due to the emergence of acquired drug resistance. We proposed a novel metabolic mechanism in cancer drug resistance where the increased capacity of the malateaspartate shuttle increased metabolic fitness, thereby facilitating cancer cells to.
Hypoxia is an environmental selection pressure that contributes to the development of mdr. Drug resistance in colorectal cancer cell lines is partially. Multiple drug resistance mdr, multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to multiple antimicrobial drugs. Stress and drug resistance in cancer university of brighton. In this model, tumours contain a small population of tumour stem cells red and their differentiated offspring. Drug resistance in cancer an overview sciencedirect topics.
Drug resistance and combating drug resistance in cancer. Drug resistance, epigenetics, and tumor cell heterogeneity. Researchers at the university of california, san diego school of medicine have discovered a biomarker called cd61 on the surface of drug resistant tumors that appears responsible for inducing tumor metastasis by enhancing the stem celllike properties of cancer cells. Original article apigenin induces apoptosis and reverses. Drug transporters in stem cells stem cells have many properties that separate them from mature, differentiated cells. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance. Increased lactate secretion by cancer cells sustains non cell autonomous adaptive resistance to met and egfr targeted therapies graphical abstract highlights d lactate production is increased in metegfr tki resistant cancer cells d caf lactate uptake stimulates hgf overexpression, driving adaptive resistance. In this study, we present data that shows differential expression levels of collagen genes and proteins in cisplatin cis, paclitaxel pac. Drug resistance, mir125b, proliferation, apoptosis, bak1 introduction gastric cancer is one of the heterogeneous malignancies, causing tremendous therapeutic burden in china. Revisiting the role of efflux pumps in multidrugresistant.
Characterization of paclitaxel resistant cancer cells for cell cycle progression and collateral resistance to other microtubuletargeting drugs. Jul 11, 2017 drug resistance is a significant therapeutic problem, from infectious diseases to cancer. Here, we aimed to identify the common signaling pathways involved in drug resistance in non. These observations reveal a potential opportunity to disrupt the drugtolerant state to more effectively suppress the acquired resistance to anticancer drugs. Cancer cells can confer resistance in these circumstances through various means. Ferroptosis at the crossroads of canceracquired drug. Tumor heterogeneity may also contribute to resistance, where small subpopulations of cells may acquire or stochastically already possess some. Therefore, survivin appears to be a pivotal protein involved in the drug resistance of cancer cells by different of. Multidrug resistance in cancer chemotherapy springerlink. However, most dcct strategies cannot coordinate the specific delivery of a drug combination in an accurately tuned ratio into cancer cells. The paradigm that drug resistance originates in the stemcell phenotype might stimulate new strategies for the development of anticancer therapies. Drug resistance is a major obstacle in cancer therapy.
Palbociclib in breast cancer and strive toward extending overall survival of treated patients. They play important roles in regulation of proliferation, differentiation, apoptosis, cell cycle, and so on,5,6 and have been proved to be associated with drug resistance in cancer. Resistance to treatment with anticancer drugs results from a variety of factors including individual variations in patients and somatic cell genetic differences in tumors, even those from the same tissue of origin. Thus, it is important to understand the characteristics and mechanisms by which cscs display resistance to therapeutic agents. The mechanisms underlying drug resistance development are incompletely understood. Role of hypoxia and glycolysis in the development of multi.
Results altered fgf expression in parental and drug resistant crc models. Systematic drug screening reveals specific vulnerabilities. Apr 27, 2017 overcoming cancer treatment resistance. Gsts assist in the development of drug resistance through direct detoxification and by inhibiting the mitogenactivated protein kinase mapk pathway 11.
Drug resistance has been studied in cancer cells grown. A singlestep, highdose selection scheme reveals distinct. One of the main causes of failure in the treatment of cancer is the development of drug resistance by the cancer cells. Both clinical and experimental aspects of drug resistance in cancer are included. Certain cell lines have become resistant to topoisomerase ii. Cancer stem cells may also play an important role in sorafenib resistance.
Because many cancer cells exhibit chromosome aneuploidy, we explored whether changes of aneuploidy status result in drug resistance. We designed this agent and various control compounds e. Drug resistance in cancer cells kapil mehta springer. About 22,240 women were diagnosed with invasive epithelial. Development of primary drug resistance can make the cancer cells susceptible for novel vulnerabilities, hence leading to additional therapeutic opportunities. New knowledge of the mechanisms of sorafenib resistance in.
Adiposederived mesenchymal stemstromal cells admsc are one of the major stromal cells in the breast cancer microenvironment that promote cancer progression. Original article expression of kap1 in epithelial ovarian. Resistance to chemotherapy is the single most important reason for treatment failure in cancer patients. Research is underway to investigate ways of reducing or preventing chemotherapy resistance. Among the various methodologies developed and employed to identify such. Two typical colorectal cancer cells, hct116 and lovo, were cultured with the chemotherapeutic drugs. Because cancer cells within the same tumor often have a variety of molecular alterations, this socalled intrinsic resistance is common. Pdf cancer stem cells and multiple drug resistance in. If the molecular basis of drug resistance could be understood, new types of treatment might be developed to cure these drug resistant cancers. This resting constitutively drug resistant cell remains at low frequency among a heterogeneous tumor mass. Resistance can occur when cancer cellseven a small group of cells within a tumorcontain molecular alterations that make them insensitive to a particular drug before treatment even begins. Apr 21, 2014 most drugs used to treat lung, breast and pancreatic cancers also promote drug resistance and ultimately spur tumor growth. Labelretaining cancer cells lrccs are a subset of cancer stem cells. Mechanisms and insights into drug resistance in cancer.
Overcoming drug resistance by targeting cancer bioenergetics. This section is intended to introduce some of the main ways in which cancer cells can resist treatments. The treatment of cancers, by definition, kills only drug sensitive cancer cells, and thus the drug resistance cancer cells survive and can expand and contribute to pathology over time. Thus, a thorough understanding of apoptotic signaling pathways and insights into apoptosis resistance mechanisms are imperative to unravel novel drug targets for the design of more effective and target selective therapeutic strategies. Increased lactate secretion by cancer cells sustains non. Cancer cells express multiple drug resistance mdr by initially developing resistance to a single anticancer drug, and slowly to various anticancer agents that are structurally similar but possess different mechanisms of. Over the past 15 years, we have gained significant far from being a phenomenon limited to the laboratory, multidrug resistance has been identified in a wide variety of newly diagnosed and recurrent human tumors. A priority in solving the problem of drug resistance is to understand the molecular mechanism of how a drug induces the resistance response within cells. Original article mir125bmediated bak1 downregulation.
However, secondary resistances towards other drugs may also arise. Given a large enough population of genetically varying target cells, the emergence of drug resistance is not surprising and is even unavoidable. Cscs or cancer cells with stem cell like properties represent an important target population for anticancer therapeutics as their survival following therapy is highly likely to result in disease relapse. In drug resistant breast cancer cells, high expression of mir93 and drug resistancerelated genes. Screening common signaling pathways associated with drug. The cancer stem cell hypothesis states that the cancer initiating cell is a transformed tissue stem cell, which retains the essential property of selfprotection through the activity of multiple drug resistance mdr transporters. Tumors become resistant not only to the drugs used initially, but also to those to which they have not yet been exposed. When a drug reaches a tumor, the cancer cell has an extensive arsenal of defense mechanism. The geneticnongenetic duality of drug resistance in cancer.
Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic cancerous cells, or the ability of cancer cells to survive and grow despite anti cancer therapies. Formyl peptide receptor 2 mediated chemotherapeutics drug resistance in colon cancer cells mgl for 72 h. Kap1, ovarian cancer, pgp, bcrp, drug resistance introduction ovarian cancer is one of the most fatal malignancies in women and is the leading cause of gynecological cancer deaths 1. The surviving daughter resistant cells are then compared to the parental sensitive cells using combination cell viabilityproliferation assays such as the mtt, acid phosphatase, or clonogenic assays. How cancer cells, with strong plasticity, orchestrate their adaptive response under sublethal drug exposure remains largely unknown. The csc model has fundamental implications for cancer therapeutics and drug resistance. Cancer stem cells cscs in drug resistance and their. Beside compound mutations in the alk kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. Wnt pathway is involved in 5fu drug resistance of colorectal cancer.
Cancer drug resistance is an open access journal, focusing on pharmacological aspects of drug resistance and its reversal, molecular mechanisms of drug resistance and drug classes, etc. Cancer is caused by disruptions to the normal processes that regulate cell division. Many drugs have been designed or discovered and used to kill cancer cells. Resistance potential assay on all parental cell lines used in the study. Properties of the small group of cancer cells called tumorinitiating or cancer stem cells cscs involved in drug resistance, metastasis and relapse of cancers can significantly affect tumor therapy. This is a very serious problem that may lead to recurrence of disease or even death. Original article a novel camptothecin analogue fl118 reduces. To address these limitations, the present work reports the engineering of circular bivalent aptamerdrug conjugates cb. Development of multidrug resistance mdrthe resistance to multiple, structurally unrelated compoundsis a. Cancer cells may develop a mechanism that inactivates the drug. These results suggest that reliable drug resistant human ovarian cancer cell lines can be successfully established by this method. Background the development of multi drug resistant mdr cancer is a significant challenge in the clinical treatment of recurrent disease. Chemotherapy resistance can arise due to several host or tumorrelated factors. Patients would respond to therapy initially because the majority of the tumor cells are sensitive to the drug.
Apr 20, 2014 cancer stem cells linked to drug resistance by university of california san diego when lung cancer cells become drug resistant, tumor cells return as shown in brown. While it is widely held that the phenomenon is genetic in nature, emerging evidence suggests that nongenetic mechanisms may also be important. A2780, a2780cp, cell line model, cisplatin, ovarian cancer, resistance induction. The different mechanisms of cancer drug resistance. Data obtained from various sources indicate that multiple mechanisms contribute to drug resistance. To elucidate the genetic factors that regulate sensitivity to anti cancer drugs, we performed crisprcas9 knockout screens for resistance to a spectrum of drugs. Article cancer lipid metabolism confers antiangiogenic drug resistance graphical abstract highlights d tumors grown in adipose tissues tend to be aad resistant d aad induces hypoxia and limits glucose supply and induces lipolysis d tumor cells switch from glycolysis to fao metabolism upon aad treatment d dual targeting angiogenesis and fao increases antitumor. Mechanisms of cancer drug resistance and sensitivity u54 rfaca17009.
Adrenaline was shown to upregulate multi drug resistance 1 mdr1 in breast cancer cells, and reduce sensitivity to paclitaxel through a reduction of accumulation of the drug within the cell. Cancer stem cells and multiple drug resistance in breast cancer article pdf available in science and culture 8034. However, most current research is focused on tumorspecific factors and specifically genes that. Furthermore, at least in some cases, refractoriness to treatment can be reversed by epigenetic reprogramming, and. Novel compounds line up to combat drug resistance in. However, most current research is focused on tumorspecific factors and specifically genes that handle expression of. The design of cancer chemotherapy has become increasingly sophisticated, yet there is no cancer treatment that is 100% effective against disseminated cancer. Bone marrow suppression often determines the upper limit of tolerable chemotherapy. One form of mdr is related to a reduction of drug accumulation in the resistant cells 7. Cancer cells become resistant to anticancer drugs by several mechanisms. Pgp expression and stability are tightly regulated and advantageous to tumor cell progression. The types most threatening to public health are mdr bacteria that resist multiple antibiotics.
From in vitro tissue culture and in vivo xenograft studies with drugresistant human cancer cell lines. Generation of cisplatinresistant ovarian cancer cell lines. The most common reason for acquisition of resistance to a broad range of anticancer drugs is expression of one or more energydependent transporters that detect and eject anticancer drugs from cells, but other mechanisms of resistance including insensitivity to druginduced apoptosis and induction of drugdetoxifying mechanisms probably play an important role in acquired anticancer drug resistance. The development of drug resistance is one reason that drugs are often given in combination. Formyl peptide receptor 2 mediated chemotherapeutics drug. Cancer chemotherapy resistance mdr is the innate andor acquired ability of cancer cells to evade the effects of chemotherapeutics and is one of the most pressing major dilemmas in cancer therapy. In this study, we report a smallmolecule targeted drug conjugate, compound c1, that circumvents drug resistance in mdr cells even at low doses. In the present study, a novel selenadiazole derivative has been evaluated and found to be able to antagonize the doxorubicin dox resistance of mcf7 cells under simulated diabetes conditions. Cell viability was determined using cell counting kit8 cck8 according to the manufacturers instructions. Original article reversing drug resistance of cisplatin by. Novel compounds line up to combat drug resistance in cancer cells. Apigenin can enhance the chemosensitivity of ovarian can cer sensitive cells and drug resistant cells. Diverse resistance mechanisms to the thirdgeneration alk. Previous studies on the effects of admsc on breast cancer metastasis and drug resistance, using twodimensional 2d cultures, remained inconclusive.
Importantly, tumor drug resistance seems to be closely. Original article reversing drug resistance of cisplatin by hsp90 inhibitors in human ovarian cancer cells zhengmao zhang 1, zhen xie, guangyu sun, pingfang yang 1, jia li, hongfang yang1, shuang xiao1, yang liu 1, hongbing qiu, lijun qin, chao zhang2, fenghua zhang3, baoen shan2. Clinically, drug resistance may develop either prior to drug therapy, or due to drug therapy. Categories of mechanisms that can enable or promote direct or indirect drug resistance in human cancer cells. In a mouse model of psychological stress the concentrations of both cortisol. Defective or inefficient apoptosis is an acquired hallmark of cancer cells. Systematic functional identification of cancer multidrug. Using clinical drug resistance to kill cancer cells. Cancer cells express multiple drug resistance mdr by initially developing resistance to a single anticancer drug, and slowly to various anticancer agents that are structurally similar but possess different mechanisms of action. Evolution of resistance to cancer therapy projects at harvard. Drugresistant cell models are developed in the laboratory by repeatedly exposing cancer cells growing in cell culture to drugs. The paradigm that drug resistance originates in the stem cell phenotype might stimulate new strategies for the development of anticancer therapies. Original article dicer reverses the chemotherapy drug.
The role of autophagy and apoptosis in the drug resistance of cancer. Many cancer cells, including mdr cells, resort to glycolysis for energy acquisition. Cancer cell lines for drug discovery and development. Cancer drug resistance is a major cause of treatment failure. Since the vast majority of patients dying of cancer will have had anticancer therapy. The metabolic intermediates can supply cancer cells with membrane phospholipids, with energy through the. One way cancer cells accomplish this is by catching the intruding drug and throwing it out of the cell before it can act.
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