Overcome cancer drug resistance by targeting epigenetic. Although the tumor stroma in solid tumors like gastric cancer gc plays a crucial role in chemo resistance, specific targets to inhibit the interaction between the stromal and cancer cells have not yet been utilized in clinical practice. Compared with various controls, the lead conjugate exhibits cancer selective activation, restores. Targeting multidrug resistance in cancer md anderson cancer. Targeting the achilles heel of multidrugresistant cancer. Jul 19, 2011 chemotherapy is currently one of the most effective ways to treat metastatic cancers. Mirkin and abdelhadi rebbaa cancer res november 15 2005 65 22 1018310187. Targeting multidrug resistance in cancer by natural. The remaining cancer cells would grow again, resulting in. Mdr is a phenotype that tumor cells acquire, which confers resistance to certain chemotherapy drugs, as well as concurrent crossresistance to additional antitumor drugs that have different structures or. This concept was first considered when bacteria became resistant to certain antibiotics, but since then similar mechanisms have been found to occur in other diseases, including cancer. Reversal of abc drug transportermediated multidrug. In most cases, multiple drugs are used, as resistance to. Progress in understanding the molecular basis of drug resistance in cancer promises more effective treatments.
Size changeable nanocarriers with nuclear targeting for effectively overcoming multidrug resistance in cancer therapy xing guo key laboratory of advanced technologies of materials, ministry of education, school of materials science and engineering, southwest jiaotong university, chengdu, 610031 p. According to who, these resistant microorganisms like bacteria, fungi, viruses, and parasites are. The emergence of drug transportermediated multidrug. This results in delayed prodrug activation and allows drug efflux mechanisms to be evaded. To establish whether sirt1 could be associated with development of drug resistance in cancer, we used various drugsensitive and drugresistant cancer cell lines representing neuroblastoma, osteosarcoma, mammary, and ovarian cancinomas 9. Novel nanopomegranates based on astragalus polysaccharides for targeting er. Multidrug resistance mdr has been intensively studied, and one of the most prominent mechanisms underlying mdr is overexpression of adenosine triphosphate atpbinding cassette abc transporters. An update on circumventing multidrug resistance in cancer by. Recently, his laboratory has evaluated the role of other abc transporters in multidrug resistance in cancer cells and has begun. Rapid development of multidrug resistance mdr against current therapies is a major barrier in the treatment of cancer. Overcoming multidrugresistant cancer with smart nanoparticles. Multidrug resistance in cancer chemotherapy springerlink. The present study aims to determine whether cancer associated fibroblasts cafs, a major component of the tumor stroma, confer chemotherapeutic resistance. A major obstacle to successful chemotherapy is the development of cellular resistance to multiple.
Intracellular entry of drugloaded liposomes via endocytosis, followed by release of entrapped agent in cytoplasm 11, is an alternative route of drug entry that may enable bypassing pgpmediated efflux. In summary, our results have demonstrated that targeting upar by crisprcas9based genome editing causes knockout of upar in human cancer cell lines, resulting in attenuation of cell proliferation, migration, invasion and multidrug resistance. Nuclear delivery of doxorubicin via folatetargeted liposomes. Targeting multidrug resistance in cancer researchgate. Mdr in cancer patients will eventually lead to the failure of cancer treatment. Xiaoqian yang, xiaoduan li, zhenfeng duan and xipeng wang affiliation. Antimicrobial categories are classifications of antimicrobial agents based on their mode of action and specific to target organisms.
Over the past 15 years, we have gained significant insight into one of the mechanisms responsible for this process. In most cases, multiple drugs are used, as resistance to single agents occurs almost universally. The multidrug resistance1 mdr1 gene product, pglycoprotein pgp, and the multidrug resistancerelated proteins mrps are members of the adenosine triphosphate atpbinding cassette abc transporter gene superfamily that regulates the trafficking of drugs, peptides, ions, and xenobiotics across cell membrane barriers. Targeting multidrug resistance in cancer gergely szakacs, jill k. Targeting multidrug resistance in cancer by natural chemosensitizers ahmed r. Gastric cancer gc is the second most common cause of death from cancer in the world, and little improvement in longterm survival has been achieved over decades 1. The engineered round nanoparticle is made of several layers. Targeting multidrug resistance in cancer by natural chemosensitizers.
Circulating tumor cells and drug history in primary breast cancer patients. At present, chemotherapy remains the optimal choice for cancer therapy, and tumor multidrug resistance mdr is a major factor that reduces the efficacy of chemotherapy. Size changeable nanocarriers with nuclear targeting for. Applications of nanoparticle drug delivery systems for the. However, of the various mechanisms that are involved in conferring resistance, upregulation of drug efflux atpbinding cassette abc transporters, such as pglycoprotein abcb1, multidrug resistance protein 1 abcc1 and abcg2, has become a major obstacle to cancer chemotherapy and seriously.
Overcome cancer drug resistance by targeting epigenetic modifications of centrosome 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. Nanodrug delivery in reversing multidrug resistance in. Coated mesoporous silica nanoparticles for lysosome. In the classic model of multidrug resistance, a membraneresident glycoprotein, termed pglycoprotein, acts as a drug efflux pump, lowering intracellular drug levels to sublethal concentrations 5,6. An update on circumventing multidrug resistance in cancer by targeting pglycoprotein volume. Multiple drug resistance mdr is a major factor in the failure of many chemotherapeutic agents and is a major challenge in cancer chemotherapy. 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 anticancer therapies. Targeting the multidrug resistance1 transporter in aml. Safe and effective reversal of cancer multidrug resistance.
Targeting ceramide metabolisma strategy for overcoming. Multidrug resistance mdr in cancer is a phenomenon that occurs when cancer cells become simultaneously resistant to structurally unrelated chemotherapeutic agents. The development of multidrug resistance mdr in cancer patients driven by the overexpression of atpbinding cassette abc transporter abcb1 or abcg2 in cancer cells presents one of the most. A major obstacle for successful management of patients with colorectal carcinoma crc is resistance to anti cancer cytotoxic treatments. Multidrug resistance an overview sciencedirect topics. Szakacs g1, paterson jk, ludwig ja, boothgenthe c, gottesman mm. Targeting multidrug resistance in cancer md anderson. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance there are two general causes of antineoplastic therapy failure. Targeting a sirt5positive subpopulation overcomes multidrug. Drug resistance in cancer is a wellknown phenomenon that results when cancer.
The main molecular mechanism of mdr is overexpression of protein transporters. The bestcharacterized cause of drug resistance involves the overexpression of p. Control of multidrug resistance gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1 fei chu, pauline m. Stimuliresponsive nanomedicines for overcoming cancer. To investigate this issue, here we identified that microrna. Chemotherapy is one of the most effective treatments for advanced lung adenocarcinoma. Compared with various controls, the lead conjugate exhibits cancerselective activation, restores. Received 2 june 20 revised 4 june 20 accepted 6 june 20 available online 8 august 20.
Dec 14, 2016 safe and effective reversal of cancer multidrug resistance using sericin. The current strategy centers around a conjugate that triggers a reprogramming of the mitochondrial metabolism. Ambudkar laboratory of cell biology, center for cancer research, national cancer institute, national institutes of health, bethesda, md 20892. For example, if multidrug resistant shigella came in contact with escherichia coli, either in a test tube or in the intestines, a high percentage of the e. Cancer cells develop multiple mechanisms to evade drug toxicity 14. One of the most common pathways leading to multidrug resistance is through the overexpression of antiapoptotic bcl2 family proteins. Despite research efforts to develop compounds that inhibit the efflux activity of abc. An update on circumventing multidrug resistance in cancer. However, cancerous cells frequently develop multidrug resistance mdr. Article pdf available december 2019 with 303 reads. Targeting multidrug resistance in cancer request pdf. Evaluation of current strategies chungpu wu, anna maria calcagno, and suresh v. The two publications report on the engineering of two separate nanoparticles that test different strategies for achieving chemosensitization of cancer cells.
The journal focuses on pharmacological aspects of drug resistance and its reversal, including drug design, drug delivery, drug distribution and cellular drug resistance, etc. Far from being a phenomenon limited to the laboratory, multidrug resistance has been identified in a wide variety of newly diagnosed and recurrent. Here, we identified a mechanism of multidrug resistance in wildtype kras crcs based on the survival of a cell subpopulation characterized by sirt5 expression. Intracellular entry of drugloaded liposomes via endocytosis, followed by release of entrapped agent in cytoplasm, is an alternative route of drug entry that may enable bypassing pgpmediated efflux. This resistance, referred to as multidrug resistance, may result from the overexpression of mrp1, which can confer cellular resistance to natural product drugs, including anthracyclines, vinca alkaloids, and epipodophyllotoxins 1, 2, 3. Novel nanopomegranates based on astragalus polysaccharides. Targeted multidrugresistance reversal in tumor based on. Targeting the achilles heel of multidrugresistant cancer by exploiting the fitness cost of resistance gergely szakacs.
Control of multidrug resistance gene mdr1 and cancer. Targeting the achilles heel of multidrugresistant cancer by exploiting the. Multidrug resistance mdr and adverse side effects are the major challenges facing cancer chemotherapy. Multiple drug resistance mdr, multidrug resistance or multiresistance is antimicrobial resistance shown by a species of microorganism to at least one antimicrobial drug in three or more antimicrobial categories. Drug efflux pumps expressed on human cancer cells majorly contribute to mdr sharom, 1997. Gopalakrishna pillai, in applications of targeted nano drugs and delivery systems, 2019. Following prolonged chemotherapy, mdr protein 1 mdr1 and cd3 increase in crc, but the. Microrna106a induces multidrug resistance in gastric. Statistics on cancer incidence and mortalities indicate that this disease still has a fatal outcome for a majority of patients due to nonsufficient treatment. Abc transporters as a causal determinant of drug resistance in cancer stem cells clinical drug resistance as we now understand is multifactorial involving alteration in drug targets, inactivationdetoxi cation of the drug, decreased. Recent studies have shown that multidrug resistance may be induced by the high stemness of cancer cells. Targeting this side population thus may provide an alternate approach to cancer therapy. However, of the various mechanisms that are involved in conferring resistance, upregulation of drug efflux atpbinding cassette abc transporters, such as pglycoprotein abcb1, multidrug resistance protein 1 abcc1 and abcg2, has become a major obstacle to cancer chemotherapy and seriously affects the.
Multiple drug resistance an overview sciencedirect topics. The drug targets multidrug resistance, angiogenesis, invasion, and proteasome. Multidrug resistance mdr that occurs in cancer cells constitutes one of the major reasons for chemotherapy failure. Microrna106a induces multidrug resistance in gastric cancer. The present study aims to determine whether cancerassociated fibroblasts cafs, a major component of the tumor stroma, confer chemotherapeutic resistance. During treatment, cells susceptible to chemotherapy are killed and generally a few cells in the tumor remain and become resistant to drugs. The incel multidrug resistance inhibitor is currently being tested in combination with chemotherapy in five phase ii clinical trials targeting breast cancer, ovarian cancer, soft tissue sarcoma. Szakacs and others published targeting multidrug resistance in cancer find, read and cite all the research you need on researchgate. One of the crucial challenges in the clinical management of cancer is resistance to chemotherapeutics.
Multidrug resistance, pglycoprotein, pglycoprotein inhibitor, drug resistant models establishment. This phenomenon has been termed multidrug resistance mdr, which occurs in a majority of cancer patients. Pdf targeting malignancies with disulfiram antabuse. Overcoming multidrug resistance in cancer stem cells. Minimum hyaluronic acid ha modified magnetic nanocrystals with less facilitated cancer migration and drug resistance for targeting cd44 abundant cancer cells by mr imaging. Szakacs g 1, paterson jk, ludwig ja, boothgenthe c, gottesman mm. An old drug, antabuse disulfiram, used for decades in alcohol aversion therapy, and its metabolite ditiocarb were shown from 1970s to suppress cancer growth in vivo and even in human patients.
Key words cancer, multidrug resistance, abc transporters, drug transport. Targeting upar by crisprcas9 system attenuates cancer. The ultimate emergence of multidrug resistance remains a severe limitation of chemotherapy treatment for patients with cancer. These efflux pumps belong to atpbinding cassette abc family and include a pgp also known as multidrug resistance protein 1 mdr1 or cluster of differentiation 243 cd243 a atpbinding cassette subfamily b member 1 encoded in human by abcb1 gene b.
Jan 22, 2019 a specific form of cellular drug resistance in cancer is termed multi drug resistance mdr. Multidrug resistance mdr to chemotherapy presents a major obstacle in the treatment of cancer patients, which directly affects the clinical success rate of cancer therapy. This is a phenomenon by which cancer cells become crossresistant to a wide variety of structurally and pharmacologically unrelated cancer cytotoxic drugs such as vinblastine, paclitaxel, and doxorubicin callies et al. Pdf targeting multidrug resistance in cancer by natural. Multidrug resistance markers pglycoprotein, multidrug resistance protein 1, and lung resistance protein in nonsmall cell lung cancer. Reversal of abc drug transportermediated multidrug resistance in cancer cells. The human atpbinding cassette transporter multidrug resistance protein 1 mrp1, encoded by, was initially identified because of its ability to confer multidrug resistance in lung cancer cells. Wed like to understand how you use our websites in order to improve them. Department of gynecology, shanghai first maternity and infant hospital affiliated tongji university, shanghai 201204, department of gynecology, shanghai first maternity and infant hospital. Cells free fulltext targeting the multidrug transporter. Review article overcoming multidrug resistance in cancer stem. Targeting cd3 reverses drugresistance via the aktnf. Nuclear delivery of doxorubicin via folatetargeted.
Drug resistance is a wellknown phenomenon that results when diseases become tolerant to pharmaceutical treatments. Effective treatment of metastatic cancers usually requires the use of toxicchemotherapy. Though chemotherapy is the most common treatment for gc, multidrug resistance mdr limited the effect of chemotherapy, which is caused by the devel. Review article overcoming multidrug resistance in cancer. In 1960s, several japanese researchers showed that multipledrug resistance could be transferred between shigella and other bacteria. Mdr is the intrinsic or acquired simultaneous resistance to unrelated therapeutics, and is arguably one of the largest barriers to the successful chemotherapeutic treatment of cancer 1,2.
Oct 01, 2004 the multidrug resistance1 mdr1 gene product, pglycoprotein pgp, and the multidrug resistancerelated proteins mrps are members of the adenosine triphosphate atpbinding cassette abc transporter gene superfamily that regulates the trafficking of drugs, peptides, ions, and xenobiotics across cell membrane barriers. Targeting multidrug resistance in cancer by natural chemosensitizers article pdf available december 2019 with 283 reads how we measure reads. The remaining cancer cells would grow again, resulting in tumor relapse and metastases. The options available for cancer treatment include chemotherapy, which still commands a leading position in clinical oncology.
Targeting delivery in mice jia liu research center for tissue engineering and regenerative medicine, union hospital, tongji medical college, huazhong university of science and technology, wuhan, 430022 china. Our study offers valuable evidences for the role of upar in cancer malignancy and drug resistance. A major obstacle for successful management of patients with colorectal carcinoma crc is resistance to anticancer cytotoxic treatments. In cancer chemotherapy, drugsensitive cells are killed whereas drug resistant cells are left. Hence, our research has focused on developing antiapoptotic bcl2 inhibitors that can eliminate drug.
Mdr is mainly due to the overexpression of abc transporters which extrude chemotherapeutic drugs outside of cancer cells. Therefore, cancer drug resistance is a major impediment in medical oncology resulting in a failure of a successful cancer treatment. Targeting multidrug resistance protein 1 mrp1, abcc1. Resistance to chemotherapy is the single most important reason for treatment failure in cancer patients. Drug resistance represents a major challenge in the treatment of cancer, and agents with the capacity to overcome drug resistance are urgently needed. Targeting the achilles heel of multidrugresistant cancer by. Magnetic tandem apoptosis for overcoming multidrugresistant cancer. Overexpression of antiapoptotic bcl2 proteins has been implicated in development of cancer and drug resistance. Magnetic tandem apoptosis for overcoming multidrug resistant cancer. Current research aims to improve the efficiency of chemotherapy, whilst reducing toxicity to prolong the lives of cancer patients. Multidrug resistance mdr is defined as insensitivity or resistance of a microorganism to the administered antimicrobial medicines which are structurally unrelated and have different molecular targets despite earlier sensitivity to it 1, 2. Targeted multidrugresistance reversal in tumor based on pegpllplga polymer nano drug delivery system liting guo,1 haijun zhang,1 fei wang,1 ping liu,1 yonglu wang,1,2 guohua xia,1 ran liu,1 xueming li,2 haixiang yin,2 hulin jiang,3 baoan chen1 1department of hematology and oncology key department of jiangsu medicine, the affiliated zhongda hospital, medical school of southeast.
Multidrug resistance is the major obstruction for successful chemotherapy even with targeted drugs orand combination chemotherapy. Combined therapy targeting both cscs and most tumor cells might be required to reduce drug resistance. Many cancers develop resistance, resulting in minimal cancer cell death and production of drugresistant tumors. In populations of cancer cells exposed to chemotherapy more than one of these mechanisms of multidrug resistance may be present. Pdf effective treatment of metastatic cancers usually requires the use of toxic chemotherapy. Although the tumor stroma in solid tumors like gastric cancer gc plays a crucial role in chemoresistance, specific targets to inhibit the interaction between the stromal and cancer cells have not yet been utilized in clinical practice. Antifolate resistance mediated by the multidrug resistance. Overcoming drug resistance by targeting cancer bioenergetics. Drug resistance and combating drug resistance in cancer. Chemotherapy is currently one of the most effective ways to treat metastatic cancers. Individual specificity with regard to variations in absorption, metabolism and delivery of drugs to target. Microrna106a induces multidrug resistance in gastric cancer by targeting runx3 yi zhang, qiping lu, xun cai.