Mechanisms of chemotherapeutic drug resistance in cancer. Clonal evolution gradually leads to aggressiveness of the cancer and resistance to treatment. Dna repair and resistance to cancer therapy intechopen. Aguilar, in nanomaterials for medical applications, 20. Drug transporters in stem cells stem cells have many properties that separate them from mature, differentiated cells. The adr intracellular accumulation and releasing were explored using fcm assay. The experiments described above indicate that endogenous hyaluronantumor cell interactions are a crucial component of the regulation of multidrug resistance in cancer cells and that the most likely mechanism whereby hyaluronan acts is by stimulating the pi 3kinase and map kinase cell survival pathways, leading to various antiapoptotic. Multidrug resistance in cancer chemotherapy springerlink. Anyone has any gooddetailed protocols on developing drugresistant cancer cell lines. Understanding cancer drug resistance by developing and.
Once inside the breast cancer cell, a fourth component called curcumin. Overcoming drug resistance in cancer chemotherapy by using nms as delivery systems is a very hot area of research in this century. Thus elevated levels of ape1 in cancer cells have been postulated to be a reason for chemotherapeutic resistance 81, 83, 84. Most drugs used to treat lung, breast and pancreatic cancers also promote drugresistance and ultimately spur tumor growth. The results revealed that degs between parental and resistant cells. Although, quite often multidrug resistance is associated to the overexpression of the membrane efflux pump pglycoprotein, other mechanisms may account for the observed resistance of dreng2 and ddreng2 cells. Overcoming multidrugresistant cancer with smart nanoparticles overcoming multidrugresistant cancer with smart nanoparticles share. Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and.
Because cancer cells within the same tumor often have a variety of molecular alterations, this socalled intrinsic resistance is common. As shown in table 1, the ic50 values of mir27a antagomir cells for vcr, adr and 5flu were significantly decreased as compared with control cells. Measuring cancer drug sensitivity and resistance in. Cisplatin resistance in the cisplatinresistant cell line a549ddp was. Cancer cells may develop a mechanism that inactivates the drug. The inability of cancer drugs to destroy metastatic tumors is the major reason why cancer therapy fails. Novel compounds line up to combat drug resistance in. Many drugs have been designed or discovered and used to kill cancer cells. Over the past 15 years, we have gained significant insight into one of the mechanisms responsible for this process.
Neoplastic resistance cancer cells also have the ability to become resistant to multiple different drugs, and share many of the same mechanisms. Cisplatin ddp is a platinumbased firstline anticancer drug with wide. Evolution of cancer can shed light on drug resistance uc. Acquired drug resistance, anticancer drugs, cancer drug resistance.
Hence, the evaluation of cellular defense mechanisms is essential in the establishment of new chemotherapeutics. Larger cell line panels may better reflect the complex processes of resistance formation in urothelial cancer cells. In view of these facts, it is important to document the mechanisms of drug resistance and understand which are the dominant. New molecules kill multidrug resistant cancer cells. One way cancer cells accomplish this is by catching the intruding drug and throwing it out of the cell before it can act.
Pdf overcoming multidrug resistance in cancer stem cells. Another example of alterations in signaling mechanisms is tamoxifen resistance in breast cancer. Cancer drug resistance cancer drug discovery and development 2006th edition. Factors of the host organism such as poor absorption and rapid metabolism can reduce the total concentration of the drug in the gastrointestinal tract, blood stream, or the tumor itself. Specific cell membrane transporter proteins are implicated in intrinsic drug resistance by altering drug transport and pumping drugs out of the tumor cells. Drug resistance in cancer an overview sciencedirect topics. Cancer cell lines for drug discovery and development. The ability of several of these membrane proteins to transport a wide range of anticancer drugs out of cells and their presence in many tumors make them prime suspects in unexplained cases of drug resistance, although proof that they contribute to. Nih funding opportunities and notices in the nih guide for grants and contracts. Resistance of cancer cells emerges due to two general mechanisms gottesman, 2002. There are also new findings on tumor immune escape mechanisms, gene amplification in drug resistance, the molecular determinants of. Notably, abcb1 expression was detected in two gemcitabineresistant cell lines although gemcitabine is not an abcb1 substrate.
However, their clinical relevance remains controversial. Drugresistant urothelial cancer cell lines display. Numerous studies have aimed to establish the role of drug transporter pumps in mdr and to link their expression to response to chemotherapy. Researchers at the university of california, san diego school of medicine have discovered a biomarker called cd61 on the surface of drugresistant tumors that appears responsible for inducing tumor metastasis by enhancing the.
Chemotherapy resistance can arise due to several host or tumorrelated factors. Iap family proteins promote apoptosisresistance iaps are a pivotal class of prosurvival factors that suppress apoptosis against a large variety of apoptotic stimuli, including chemotherapeutic agents, radiation, and immunotherapy in cancer cells35. During chemotherapy, when using certain drugs, the tumor cells are affected by toxic and oxidative stress, which stop their functioning. Drug resistance continues to be the principal limiting factor to achieving cures in patients with cancer.
Far from being a phenomenon limited to the laboratory, multidrug resistance has been identified in a wide. Unfortunately, novel drug development by cell and molecular biologists, often neglects the pharmacology of a drug. Increased efflux of drug as by pglycoprotein, multidrug resistanceassociated protein, lung resistancerelated protein, and breast cancer resistance protein2. If all cells within a tumor are able to divide and inherit genetic changes to the next generation, there is a strong selection pressure for the cells to develop resistance those that are not fit will not survive. Since the vast majority of patients dying of cancer will have had anticancer therapy, both c. During this progression, cancer cells not only change their response to the drug being used to treat the cancer, but also to many other drugs. Resistance to chemotherapy is the single most important reason for treatment failure in cancer patients. A growing number of studies have revealed that mechanisms underlying the development of drug resistance in cancer cells are manifold and complex and very likely are dependent on cell and microenvironment context. The tumor microenvironment is fundamentally involved in the response of a tumor to anticancer therapies. Drug combinations to overcome treatment resistance. There is no cancer therapy known that does not select for resistance, he says.
The human multidrug resistanceassociated protein mrp family currently has seven members. Lung cancer, resistance to gemcitabine and cisplatin, transition phenotypes. For analysis of multidrug resistance, a major barrier to effective cancer chemotherapy, we. 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. Research is underway to investigate ways of reducing or preventing chemotherapy resistance. One of the main causes of failure in the treatment of cancer is the development of drug resistance by the cancer cells. Chemotherapy is one of the major treatment methods for cancer. Identifying clinically relevant drug resistance genes in. There are several mechanisms including inactivation of. More than 30 years ago, they discovered that in some cases, when patients go from being sensitive to resistant to treatment, their cancer cells start to overexpress abc. Molecular mechanisms of tumor cell resistance to chemotherapy. Overcoming multidrugresistant cancer with smart nanoparticles. The different mechanisms of cancer drug resistance.
The problem of drug resistance in cancer has strong similarities to the field of. We find that cancerspecific drugs do not show higher efficacies in cell lines. Various tumor clones have different capabilities to proliferate in the absence or presence of drugs figure figure1,1, making the genetic landscape of the tumor clones highly dynamic 21. Targeting multidrug resistance in cancer by natural. Downregulation of mir27a might reverse drug resistance of gastric cancer cells.
Reversal of drug resistance in breast cancer cells by. One of the major problems in pdac therapy is multidrug resistance, which not only leads to a reduced efficacy of chemotherapeutic drugs but can also favor the survival and expansion of resistant cancer cells, thus contributing to relapses that worsen outcomes over time choi, 2005. However, er signaling has a complex interaction with other growth signaling pathways in breast cancer cells, thus enabling drug resistance through various mechanisms. Moreover, the gradual acquisition of specific genetic and epigenetic abnormalities in cancer cells could contribute greatly to acquired drug resistance. Multidrug resistance was first described in 1970 after selection of chinese hamster ovarian cancer cells exposed to increasing concentrations of actinomycin d. Overcome cancer cell drug resistance using natural products. Studies on mechanisms of cancer drug resistance have yielded important information. Abcg 2 abcb 1 anticancer drug multidrugresistant cancer cell drug in. Nanodrug delivery in reversing multidrug resistance in. A specific form of cellular drug resistance in cancer is termed. These studies have shown that dna methyltransferase inhibitors can increase the 5fu sensitivity of 5fu resistant colorectal cancer cells. The challenge of drug resistance in cancer treatment. We assess whether drug sensitivity in cancer cell lines is able to discriminate tissue specificity.
Selective nanocarrier targeting to tumor overcomes doselimiting side effects, lack of selectivity, tissue toxicity, limited drug access to tumor tissues, high drug doses, and emergence of multiple drug resistance with conventional or combination chemotherapy. Sorger 1hms lincs center, laboratory of systems pharmacology, department of systems biology, harvard medical school, boston, massachusetts 2these authors contributed equally to the work described here measuring the potencies of smallmolecule. This section is intended to introduce some of the main ways in which cancer cells can resist treatments. This is a very serious problem that may lead to recurrence of disease or even death. Stromal cells confer drug resistance to breast cancer cells in a. Regulation of multidrug resistance in cancer cells by.
Downregulation of mir27a might inhibit proliferation and. In figure 1, a schematic overview of potential resistance mechanisms is given. Understanding cancer drug resistance by developing and studying resistant cell line models. Categories of mechanisms that can enable or promote direct or indirect drug resistance in human cancer cells. The development of multidrug resistance mdr and subsequent relapse on therapy is a widespread problem in breast cancer, but our understanding of the underlying molecular mechanisms is incomplete. However, failure in chemotherapy is not uncommon, mainly due to doselimiting toxicity associated with drug resistance. Resistance of cancer cells towards chemotherapy is the major cause of therapy failure. With cancer drug resistance, we aim to establish a forum for papers dealing with all aspects of drug resistance. Colorectal cancer lines selected for resistance to 5fu by longterm 5fu treatment have been used to investigate whether epigenetic factors contribute to drug resistance. Over 10 million scientific documents at your fingertips. Inhibition of ape1 has been shown to increase cell killing and apoptosis and also to sensitize cancer cells to chemotherapeutic agents, and thus ape1 is considered as a molecular target in therapeutics 85, 86. Measuring cancer drug sensitivity and resistance in cultured cells mario niepel, 1,2marc hafner, mirra chung, 1and peter k. 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.
Cancer cells can confer resistance in these circumstances through various means. Various mechanisms that have been proposed include enhanced intracellular concentration of the drug by endocytosis, 1. Certain cell lines have become resistant to topoisomerase ii. However, most current research is focused on tumorspecific factors and. The cancer cells may learn how to repair the dna breaks caused by some anticancer drugs. The development of drug resistance is one reason that drugs are often given in combination. Induction of transglutaminase 2 tgase 2 by epidermal growth factor egf in human breast cancer cells increases their oncogenic potential and chemoresistance. The role of tgase 2 in the development of these tumorrelated phenotypes remains to be elucidated, but it has been shown that expression of a dominantnegative form of tgase 2 reverses egf. Tamoxifen acts as an estrogen receptor er antagonist. The paradigm that drug resistance originates in the stemcell phenotype might stimulate new strategies for the development of anticancer therapies. If the molecular basis of drug resistance could be understood, new types of treatment might be developed to cure these drugresistant cancers.
Drug sensitivity in cancer cell lines is not tissue. Drug resistance in cancer cells md anderson cancer center. Additionally, researchers have determined that the bcrablinde. Using clinical drug resistance to kill cancer cells. A more diverse cancercell population is more likely to have a resistant clone, and in the environment of the therapy, it will tend to outcompete the other cancer cells. Review article overcoming multidrug resistance in cancer. The clinical relevance of these findings needs to be further investigated. Management of drug resistance is important towards successful chemotherapy.
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