Cancer cells can confer resistance in these circumstances through various means. Induction of transglutaminase 2 tgase 2 by epidermal growth factor egf in human breast cancer cells increases their oncogenic potential and chemoresistance. Cisplatin ddp is a platinumbased firstline anticancer drug with wide. 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. Categories of mechanisms that can enable or promote direct or indirect drug resistance in human cancer cells. Chemotherapy resistance can arise due to several host or tumorrelated factors. The human multidrug resistanceassociated protein mrp family currently has seven members. Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and.
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. For analysis of multidrug resistance, a major barrier to effective cancer chemotherapy, we. One way cancer cells accomplish this is by catching the intruding drug and throwing it out of the cell before it can act. Overcoming drug resistance in cancer chemotherapy by using nms as delivery systems is a very hot area of research in this century. 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. However, most current research is focused on tumorspecific factors and. However, their clinical relevance remains controversial. This is a very serious problem that may lead to recurrence of disease or even death. Multidrug resistance in cancer chemotherapy springerlink. 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. In view of these facts, it is important to document the mechanisms of drug resistance and understand which are the dominant. Thus elevated levels of ape1 in cancer cells have been postulated to be a reason for chemotherapeutic resistance 81, 83, 84. Certain cell lines have become resistant to topoisomerase ii. Understanding cancer drug resistance by developing and.
Drug sensitivity in cancer cell lines is not tissue. The challenge of drug resistance in cancer treatment. Mechanisms of chemotherapeutic drug resistance in cancer. The results revealed that degs between parental and resistant cells. A specific form of cellular drug resistance in cancer is termed. Anyone has any gooddetailed protocols on developing drugresistant cancer cell lines. Lung cancer, resistance to gemcitabine and cisplatin, transition phenotypes. However, er signaling has a complex interaction with other growth signaling pathways in breast cancer cells, thus enabling drug resistance through various mechanisms. With cancer drug resistance, we aim to establish a forum for papers dealing with all aspects of drug resistance. 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. Dna repair and resistance to cancer therapy intechopen.
The problem of drug resistance in cancer has strong similarities to the field of. Numerous studies have aimed to establish the role of drug transporter pumps in mdr and to link their expression to response to chemotherapy. 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. Resistance of cancer cells towards chemotherapy is the major cause of therapy failure. Drug resistance in cancer an overview sciencedirect topics. Pdf cancer stem cells in resistance to cytotoxic drugs. Research is underway to investigate ways of reducing or preventing chemotherapy resistance. Moreover, the gradual acquisition of specific genetic and epigenetic abnormalities in cancer cells could contribute greatly to acquired drug resistance. Novel compounds line up to combat drug resistance in. Drug resistance continues to be the principal limiting factor to achieving cures in patients with cancer. Molecular mechanisms of tumor cell resistance to chemotherapy. Management of drug resistance is important towards successful chemotherapy.
Reversal of drug resistance in breast cancer cells by. Increased efflux of drug as by pglycoprotein, multidrug resistanceassociated protein, lung resistancerelated protein, and breast cancer resistance protein2. Another example of alterations in signaling mechanisms is tamoxifen resistance in breast cancer. Clonal evolution gradually leads to aggressiveness of the cancer and resistance to treatment. 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.
Downregulation of mir27a might inhibit proliferation and. Evolution of cancer can shed light on drug resistance uc. Once inside the breast cancer cell, a fourth component called curcumin. Specific cell membrane transporter proteins are implicated in intrinsic drug resistance by altering drug transport and pumping drugs out of the tumor cells. One of the main causes of failure in the treatment of cancer is the development of drug resistance by the cancer cells. Multidrug resistance was first described in 1970 after selection of chinese hamster ovarian cancer cells exposed to increasing concentrations of actinomycin d. Far from being a phenomenon limited to the laboratory, multidrug resistance has been identified in a wide. 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. Cancer cell lines for drug discovery and development. In figure 1, a schematic overview of potential resistance mechanisms is given.
Even though the process of drug design has become exceedingly sophisticated in recent years, there is not a single drug available that is 100% effective against metastatic cancer. Cancer drug resistance cancer drug discovery and development 2006th edition. Larger cell line panels may better reflect the complex processes of resistance formation in urothelial cancer cells. Studies on mechanisms of cancer drug resistance have yielded important information. The adr intracellular accumulation and releasing were explored using fcm assay. Over the past 15 years, we have gained significant insight into one of the mechanisms responsible for this process. Pdf overcoming multidrug resistance in cancer stem cells.
Overcoming multidrugresistant cancer with smart nanoparticles. Identifying clinically relevant drug resistance genes in. Drug transporters in stem cells stem cells have many properties that separate them from mature, differentiated cells. During chemotherapy, when using certain drugs, the tumor cells are affected by toxic and oxidative stress, which stop their functioning. The paradigm that drug resistance originates in the stemcell phenotype might stimulate new strategies for the development of anticancer therapies.
Cancer cell lines have a prominent role in the initial stages of drug discovery, facilitating highthroughput screening of potential drugs. Many drugs have been designed or discovered and used to kill cancer cells. The clinical relevance of these findings needs to be further investigated. Measuring cancer drug sensitivity and resistance in. Over 10 million scientific documents at your fingertips. Downregulation of mir27a might reverse drug resistance of gastric cancer cells. Using clinical drug resistance to kill cancer cells. Targeting multidrug resistance in cancer by natural. Drug resistance in cancer cells md anderson cancer center. 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. 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. Overcoming multidrugresistant cancer with smart nanoparticles overcoming multidrugresistant cancer with smart nanoparticles share.
Tamoxifen acts as an estrogen receptor er antagonist. 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. Since the vast majority of patients dying of cancer will have had anticancer therapy, both c. Measuring cancer drug sensitivity and resistance in cultured cells mario niepel, 1,2marc hafner, mirra chung, 1and peter k. However, failure in chemotherapy is not uncommon, mainly due to doselimiting toxicity associated with drug resistance. Stromal cells confer drug resistance to breast cancer cells in a. Understanding cancer drug resistance by developing and studying resistant cell line models. Additionally, researchers have determined that the bcrablinde. 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. 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. Resistance to chemotherapy is the single most important reason for treatment failure in cancer patients.
Notably, abcb1 expression was detected in two gemcitabineresistant cell lines although gemcitabine is not an abcb1 substrate. Abcg 2 abcb 1 anticancer drug multidrugresistant cancer cell drug in. Drugresistant urothelial cancer cell lines display. There are also new findings on tumor immune escape mechanisms, gene amplification in drug resistance, the molecular determinants of. Overcome cancer cell drug resistance using natural products. Nih funding opportunities and notices in the nih guide for grants and contracts. There are many reports in the chinese literature that natural products can overcome cancer. This section is intended to introduce some of the main ways in which cancer cells can resist treatments. Drug combinations to overcome treatment resistance.
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. Chemotherapy is one of the major treatment methods for cancer. There is no cancer therapy known that does not select for resistance, he says. 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. Regulation of multidrug resistance in cancer cells by. The different mechanisms of cancer drug resistance. Neoplastic resistance cancer cells also have the ability to become resistant to multiple different drugs, and share many of the same mechanisms. 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. 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. These studies have shown that dna methyltransferase inhibitors can increase the 5fu sensitivity of 5fu resistant colorectal cancer cells. If the molecular basis of drug resistance could be understood, new types of treatment might be developed to cure these drugresistant cancers. We find that cancerspecific drugs do not show higher efficacies in cell lines. Hence, the evaluation of cellular defense mechanisms is essential in the establishment of new chemotherapeutics.
Colorectal cancer lines selected for resistance to 5fu by longterm 5fu treatment have been used to investigate whether epigenetic factors contribute to drug resistance. Various mechanisms that have been proposed include enhanced intracellular concentration of the drug by endocytosis, 1. 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. Mechanisms of cancer drug resistance and sensitivity u54 rfaca17009. The development of drug resistance is one reason that drugs are often given in combination. We assess whether drug sensitivity in cancer cell lines is able to discriminate tissue specificity.
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. 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. Because cancer cells within the same tumor often have a variety of molecular alterations, this socalled intrinsic resistance is common. Resistance of cancer cells emerges due to two general mechanisms gottesman, 2002. Animportantstrategy to overcome drug resistance in cscs would be to target the functioning of abc transporters in these cells. The tumor microenvironment is fundamentally involved in the response of a tumor to anticancer therapies. Unfortunately, novel drug development by cell and molecular biologists, often neglects the pharmacology of a drug.
There are several mechanisms including inactivation of. Aguilar, in nanomaterials for medical applications, 20. Acquired drug resistance, anticancer drugs, cancer drug resistance. Most drugs used to treat lung, breast and pancreatic cancers also promote drugresistance and ultimately spur tumor growth. Review article overcoming multidrug resistance in cancer. The cancer cells may learn how to repair the dna breaks caused by some anticancer drugs. 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. Cisplatin resistance in the cisplatinresistant cell line a549ddp was. New molecules kill multidrug resistant cancer cells. 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.
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