Ample evidence suggests that the expression of atp binding cassette abc transporters, especially the multidrug resistance protein 1 mdr1, also known as p glycoprotein or pgp, which is encoded by abc subfamily b member 1 abcb1, can confer resistance to cytotoxic and targeted chemotherapy. Furthermore, other human abc proteins capable of actively transporting various compounds. We will focus on the ability of mrps to transport anticancer drugs and the possible contribution of mrps to drug resistance in patients. Download citation abc transporters in multidrug resistance and. Understanding of human atp binding cassette superfamily. Among the several protective mechanisms for cscs, the overexpression of the atpbinding cassette abc efflux transporters is probably the most important. Specifically, pglycoprotein pgp, multidrug resistanceassociated proteins mrps, and breast cancer resistance protein bcrpabcg2 are described in more detail. This work represents the first demonstration of multidrug transport by sav1866 and suggests that sav1866 can serve as a welldefined model for studies on the molecular bases of drug.
Overexpression of certain abc transporters occurs in cancer cell lines and tumors that are multidrug resistant. Novel plant triterpenoid drug amooranin overcomes multidrug. The emergence of drug transporter mediated multidrug. Abc transporters and multidrug resistance pharmaceutical. One class of these permeases, known as multidrug resistance atp binding cassette abc transporters, translocate these molecules by. Summary membrane proteins responsible for the active efflux of structurally and functionally unrelated drugs were first characterized in higher eukaryotes. As with multidrug resistance, these contributions likely represent a hijacking of normal abc transporter functions in the efflux of endogenous metabolites and signaling molecules, however they may expand the clinical relevance of abc transporters beyond pgp, bcrp and mrp1. Molecular mechanisms and novel therapeutic drug strategies. This is clinically relevant, as tumour cells may become resistant. Multidrug resistance transporters roles in maintaining. Abctransporters multidrugresistance mdr is the chief limitation to the success of chemotherapy. Multidrug transporter proteins contribute to chemoresistance through the efflux of anticancer drugs from cancer cells.
Abc transporters as multidrug resistance mechanisms and the development of. Revisiting the role of efflux pumps in multidrug resistant. Revisiting the role of abc transporters in multidrugresistant cancer. Abc transporters and multidrug resistance ebook, 2009. Atpbinding cassette transporter genes abc transporters are known to play a crucial role in the development of multidrug. Multidrug resistance mdr in cancer cells can significantly attenuate the response to chemotherapy and increase the likelihood of mortality. Overcoming abc transportermediated multidrug resistance ncbi. Pgp, multidrug resistance protein 1 mrp1abcc1, and breast cancer resistance protein bcrpabcg2mxrabcp. The abctype multidrug transport system scrub typhus and. Chemotherapy is currently one of the most effective ways to treat metastatic cancers.
Multidrug resistance mdr is a serious problem that hampers the success of cancer pharmacotherapy. Intracellular abc transporter a3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration. According to the national cancer institute, multidrugresistance is a phenomenon where cancer cells adopt to antitumor drugs in such a. These are the classical pglycoprotein mdr1, abcb1, the multidrug resistance associated proteins mrps, in the abcc subfamily, and the abcg2 protein, an abc half transporter. Abc transporters as mediators of drug resistance and. This protein functions as a multispecific organic anion.
Multidrug resistance and abc transporters conference. This full transporter is a member of the mrp subfamily which is involved in multidrug resistance. Multidrug transporters of the abc family facilitate the export of diverse cytotoxic drugs across cell membranes. Abc transporters and multidrug resistance offers an essential resource for pharmaceutical researchers who are working to discover drugs to counteract multidrug resistance in diseases such as cancer.
Indeed, multidrug resistance mdr is a significant obstacle to effective chemotherapy. Multidrug resistance abc transporters sciencedirect. Predictions about the functions of genes in the growing number of sequenced. Abc transporters and resistance to antibiotics \ serge michalet and mariegenevi\u00e9ve dijouxfranca. Multidrug transport by the abc transporter sav1866 from. Within the abc superfamily, the mdr transporters abcb1, abcc1, abcg2 in mouse models have been proved to be valuable to investigate the biochemistry and physiological functions. Abc transporters in multidrug resistance and pharmacokinetics. The human multidrug resistance associated protein mrp family currently has seven members. A common mechanism is the overexpression of atpbinding cassette abc efflux transporters in cancer cells such as pglycoprotein pgpabcb1, multidrug resistance associated protein 1 mrp1abcc1 and breast cancer resistance protein bcrpabcg2 that limit the exposure. School of medicine, faculty of health, university of tasmania. In one comprehensive volume, this book contains a collection of the most current knowledge on the involvement of abc transporters in drug transport. Implications of abc transporters in antimicrobial therapeutic strategies. Abc proteins transport various molecules across extraand intracellular membranes. Ample evidence suggests that the expression of atpbinding cassette abc transporters, especially the multidrug resistance protein 1 mdr1, also known as.
Abc transporters and multidrug resistance boomerang books. This book gathers present knowledge on the involvement of abc transporters in drug transport and resistance. Bacterial abc transporters responsible for antibiotic resistance. Distribution and physiology of abctype transporters. The overexpression of one or more multidrug resistance mdrlinked atpbinding cassette abc drug transporters, such as abcb1 pglycoprotein, mdr1, abcc1 multidrug resistance protein 1, mrp1.
Abc genes are divided into seven distinct subfamilies abc1, mdrtap, mrp, ald, oabp, gcn20, white. Chapuy b, koch r, radunski u, corsham s, cheong n, inagaki n, ban n, wenzel d, reinhardt d, zapf a, schweyer s, kosari f, klapper w, truemper l, wulf gg. Finally, rational molecular interventions based on the abcm. There are two other abc transporters, which have been definitely demonstrated to participate in the multidrug resistance of tumors. Discovered first in cancer, the activity of pglycoprotein pgp. Novel inhibitors of abc transporters increase accumulation of. Select chapter 19 multidrug resistance protein 1 abcc1. 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. Abc transporters constitute one of the largest protein families found in all living organisms. Human multidrug resistance abc transporters are ubiquitous membrane proteins responsible for the efflux of multiple, endogenous or exogenous, compounds out of the cells, and therefore they are involved in multidrug resistance phenotype mdr. Mdr is the ability of pathologic cells, such as tumors, to withstand. Abc transporters as multidrug resistance mechanisms and. The overexpression of atpbinding cassette abc membrane transporters is a principal cause of enhanced cytotoxic drug efflux and treatment failure in various types of cancers. This book is sure to become a classic and will regularly be updated.
Other abc transporters that contribute to multidrug resistance are abcc1 mrp1 and abcg2 breast cancer resistance protein. They thus deeply impact the pharmacokinetic parameters and toxicity properties of drugs. Abc transporters and multidrug resistance wiley online books. Abc transporters are driven by atp hydrolysis and can act as exporters as well as importers. The development of resistance is a major obstacle in cancer chemotherapy and the field has been moving rapidly in terms of determining the mechanisms for blocking abc transporter mediated drug efflux by specific inhibitors and thereby overcoming multidrug resistance. The plant genome encodes for more than 100 abc transporters, largely exceeding that of. Abctype mdr transporters are relatively poorly characterized for both grampositive and negative bacteria. Multidrug resistance mdr is a major cause of chemotherapy failure. The human atpbinding cassette abc transporter superfamily. It is estimated 2025% of the epileptic patients fails to achieve good control with the different antiepileptic drugs aeds treatments, developing refractory epilepsy re. Abc transporter inhibitors in reversing multidrug resistance to chemotherapy volume. Three abc transporters appear to account for most of the reported mdr in humans. Abc multidrug transporters structure, function and role. Overcoming abc transportermediated multidrug resistance.
Overexpression of atpbinding cassette abc transporters. Multidrug resistance in cells may be partially developed due to cell membrane anchored efflux transporter proteins. We place a special emphasis on the three major groups of abc transporters involved in cancer multidrug resistance mdr. This book on candida albicans and similar pathogens provides a timely overview of the groundbreaking discoveries made in the areas of drug resistance, hostpathogen interactions, virulence, host immune system modulation, etc.
Pglycoprotein pgp, mdr1, abcb1 was the first discovered abc transporter and is likely to be responsible for the most widely observed mechanism in clinical multi drug resistance. To date, a vast number of transporters contributing to multidrug resistance mdr transporters have been reported for a large variety of organisms. Resistance to targeted abc transporters in cancer thomas. Multidrug resistance an overview sciencedirect topics. Provides uptodate research on the role of abc transporters in drugresistant. As noted above, the fda now offers guidance on measuring the interaction of novel therapies with abc transporters during clinical development. Abc transporters and multidrug resistance book, 2009.
Multidrug resistance abc transporter structure predictions. Abc transporters and resistance to antibiotics abc. The ability of several of these membrane proteins to transport a wide range of anticancer drugs out of. One class of these permeases, known as multidrug resistance atp binding cassette abc transporters, translocate these molecules by coupling druglipid efflux with energy derived from the hydrolysis of atp. It will be useful to anyone trying to stay abreast of the latest findings. The major mechanism involved in conferring mdr is the overexpression of atpbinding cassette abc transporters, which can increase efflux of drugs from cancer cells, thereby decreasing intracellular drug concentration. The year 2006 represented the 30th anniversary of the discovery of p. The atpbinding cassette abc transporters are a family of transporter proteins that are responsible for drug resistance and a low bioavailability of drugs by pumping a variety of drugs out cells at the expense of atp hydrolysis. Millernational institute of environmental health sciences, nih regulation of pglycoprotein and other abc drug transporters at the bloodbrain barrier meeting focus the meeting will cover multidrug resistance in cancer and abc. An integrative model termed the abcm model that considers the role of abc transporters during melanogenesis is introduced to account for intrinsic and acquired multidrug resistance mdr mechanisms in melanoma cells. Involvement of abc transporters in melanogenesis and the. Mouse atp binding cassette abc transporters conferring. An omic approach to identify novel druggable targets. Structure of a bacterial multidrug abc transporter nature.
Abc transporters as multidrug resistance mechanisms and the. Distribution and physiology of abc type transporters. These efflux pumps belong to the adenosine triphosphatebinding cassette abc superfamily and are actively engaged in effluxing exogenous xenobiotics and providing protection to the cell. Clinical multidrug resistance is caused by a group of integral membrane proteins that transport hydrophobic drugs and lipids across the cell membrane. The atpbinding cassette abc transporter superfamily contains membrane proteins that translocate a wide variety of substrates across extra and intracellular membranes, including metabolic products, lipids and sterols, and drugs. These proteins can recognize and transport a large number of structurally diverse compounds. The role of abc transporters in drug resistance, metabolism and. Multidrug resistance mdr transporters can be divided into two classes based on their source of energy. Clinical and therapeutic implications of multidrug resistance associated abc drug transporters dr.