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Mechanisms and Strategies to Overcome Multiple Drug Resistance in Cancer

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Mechanisms and Strategies to Overcome Multiple Drug Resistance in Cancer View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 580 (2006) 2903–2909 Minireview Mechanisms and strategies to overcome multiple drug resistance in cancer Tomris Ozben* Akdeniz University, Faculty of Medicine, Department of Biochemistry, 07070 Antalya, Turkey Received 30 January 2006; accepted 9 February 2006 Available online 17 February 2006 Edited by Horst Feldmann The cytotoxic drugs that are most frequently associated with Abstract One of the major problems in chemotherapy is multi- drug resistance (MDR) against anticancer drugs. ATP-binding MDR are hydrophobic, amphipathic natural products, such as cassette (ABC) transporters are a family of proteins that medi- the taxanes (paclitaxel and docetaxel), vinca alkaloids (vinorel- ate MDR via ATP-dependent drug efflux pumps. Many MDR bine, vincristine, and vinblastine), anthracyclines (doxorubicin, inhibitors have been identified, but none of them have been pro- daunorubicin, and epirubicin), epipodophyllotoxins (etoposide ven clinically useful without side effects. Efforts continue to dis- and teniposide), antimetabolites (methorexate, fluorouracil, cover not toxic MDR inhibitors which lack pharmacokinetic cytosar, 5-azacytosine, 6-mercaptopurine, and gemcitabine) interactions with anticancer drugs. Novel approaches have also topotecan, dactinomycin, and mitomycin C [4,6–8]. been designed to inhibit or circumvent MDR. In this review, Overexpression of ATP-binding cassette (ABC) transporters the structure and function of ABC transporters and development has been shown to be responsible for MDR [5]. Therefore eluci- of MDR inhibitors are described briefly including various ap- dation of the structure and function for each ABC transporter is proaches to suppress MDR mechanisms. Ó 2006 Federation of European Biochemical Societies. Published prerequisite for understanding how these transporters work and by Elsevier B.V. All rights reserved. for reversing MDR. One strategy for reversal of MDR in cells expressing ABC transporters is combined use of anticancer Keywords: Multidrug resistance; ATP-binding cassette drugs with chemosensitizers. Inhibitors of ABC transporters transporters; Cancer chemotherapy; Multidrug resistance can be used to enhance oral bioavailability or the brain penetra- inhibitors tion of various drugs. Downregulation of MDR transporters and circumventing MDR mechanisms are other approaches to overcome MDR [3,5]. 1. Introduction 2. ATP-binding cassette (ABC) transporters The failure of the curative treatment of cancer patients often Identifying the mechanisms leading to intrinsic or acquired occurs as a result of intrinsic or acquired drug resistance of the multidrug resistance (MDR) is important in developing more tumor to chemotherapeutic agents. The resistance of tumors effective therapies [2]. The drug resistance in cancer cells often occurs not only to a single cytotoxic drug used, but also occurs results from elevated expression of particular proteins, such as as a cross-resistance to a whole range of drugs with different cell-membrane transporters, which can result in an increased structures and cellular targets. This phenomenon is called mul- efflux of the cytotoxic drugs from the cancer cells, thus lower- tiple drug resistance (MDR). Once MDR appears, using high ing their intracellular concentrations [4,6,9]. The resistance doses of drugs to overcome resistance is ineffective, toxic effects mechanism is called typical or classical MDR when overex- appear and resistance are further stimulated. Multidrug resis- pression of the membrane efflux pumps is involved in MDR tance (MDR) severely limits the effectiveness of chemotherapy [5]. The classical MDR is due mostly to increased efflux pumps in a variety of common malignancies and is responsible for the in the cell membrane of cells pumping anticancer drugs out of overall poor efficacy of cancer chemotherapy [1–5]. cells [1–3,5]. ATP-binding cassette (ABC) transporters are a family of transporter proteins that contribute to drug resistance via *Fax: +90 242 2274495. E-mail address: [email protected] (T. Ozben). adenosinetriphosphate (ATP)-dependent drug efflux pumps [10]. Up to date, more than 100 ABC transporters from pro- Abbreviations: MDR, multidrug resistance; MRP, multidrug resistance karyotes to humans and 48 human ABC genes have been iden- protein; ATP, adenosinetriphosphate; ABC, ATP-binding cassette; tified that share sequence and structural homology [4,5,10,11]. TMD, transmembrane domains; P-gp, P-glycoprotein; MRP1, MDR related protein; BCRP, breast cancer resistance protein; ABC-P, ABC Not more than 10 of the ATP transporters are reported to con- transporter in placenta; LRP, lung resistance-related protein; MVP, fer the drug-resistant phenotype [4,9]. The functions of 16 major vault protein; CMOAT, canalicular multi-organic anion trans- genes have been determined and 14 genes are related with sev- porter; CYP3A4, Cytochrome p450 3A4; SXR, steroid and xenobiotic eral diseases present in humans [5,11,12]. Although the resis- receptor; GC, glucosylceramide; GCS, glucosylceramide synthase; tant proteins belong to the ABC superfamily, they are quite GSH, glutathione; NAC, N-acetylcysteine; BSO, DL-buthionine (S,R)-sulfoximine; HEK, human embryonic kidney; ROS, reactive different with respect to gene locus, amino acid sequence, oxygen species structure and substrate [5]. ABC proteins are present in all 0014-5793/$32.00 Ó 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.febslet.2006.02.020 2904 T. Ozben / FEBS Letters 580 (2006) 2903–2909 known living species, with a relatively conserved structure amplification and increased expression of a novel gene, the which contains a combination of conserved ABC and trans- MRP1 (ABCC1) (MDR related protein) gene in a non-P-gp membrane domains (TMDs). In mammals, the functionally ac- MDR cell line, namely a small-cell lung carcinoma cell line tive ABC proteins consist of at least four of such domains, two [10,18]. Overexpression of MRPs, other ABC proteins, causing TMDs and two ABCs. These domains may be present within MDR in mammalian cells has been also observed in several one polypeptide chain (full transporters), or within two sepa- other non-P-gp MDR cell lines. MRP1 has 3 membrane span- rate proteins (half-transporters). In this latter case, functional ning domains, 2 nucleotide binding domains and extracellular ABC transporters need the dimerization of specific half-trans- N-terminal. Both the structure and drug resistance spectra of porters [13]. High sequence homology in the ATP-binding do- MRP1 and P-gp are similar except taxanes which are poor sub- mains known as nucleotide-binding folds allows identification strates for MRP1. The second member of the multidrug resis- and classification of members of the ABC transporter family tance protein (MRP) (ABCC) family is called the canalicular [10]. These transporters use the energy released from the multi-organic anion transporter (CMOAT, MRP2) which is hydrolysis of ATP to drive the transport of various molecules involved in bilirubin glucuronide transport and confers resis- across the cell membrane [4,11]. They are involved in the trans- tance to MRP1 substrates and cisplatin. MRP3 is expressed port of many substances, including the excretion of toxins in liver and involved in the efflux of organic anions from the from the liver, kidneys, and gastrointestinal tract. It has been liver into the blood in case of biliary obstruction. MRP4 and increasingly recognized that transporter-mediated processes MRP5 transport nucleosides and confer resistance to antiret- significantly modulate drug absorption, distribution, metabo- roviral nucleoside analogs. MRP6 is a lipophilic anion pump lism and excretion [13]. In addition to their physiologic expres- with a wide spectrum of drug resistance. Among the members sion in normal tissues, many are over-expressed, in human of MRP family, only MRP1 has been widely accepted to cause tumors [4]. There are seven subfamilies classified as ABC trans- clinical drug resistance [10]. porters (ABC-A through ABC-G) that are expressed in both The latest ABC transporter involved in MDR was cloned by normal and malignant cells [10]. A number of ABC transport- Ross and Doyle in 1998 from a mitoxantrone-resistant subline ers and the chemotherapy drugs to which they have been of the breast cancer cell line MCF-7/Adr/Vp [19]. It is part of shown to confer resistance are listed in Table 1. ABCG subfamily. ABCG2 is the mitoxantrone resistance gene, breast cancer resistance protein (BCRP), or ABC transporter in placenta (ABC-P). BCRP is a half-transporter that probably 3. Structure and function of ABC transporters acts as a homo- or heterodimer in transporting cytotoxic agents [10]. A 110 kDa protein originally named lung resis- The most typical efflux pump in the cell membrane is P-gly- tance-related protein/major vault protein (LRP/MVP) is not coprotein (P-gp) having the molecular weight of 170 kDa, due an ABC transporter, but a major vault protein which consti- to the gene amplification of the normal human gene, ABCB1 tutes >70% of subcellular ribonucleoprotein particles called (MDR1) gene [5,10]. P-gp belongs to the ATP-binding cassette vaults. It is found in the cytoplasm and nuclear membrane, (ABC) family of transporters. P-gp is responsible for trans- not on the cell membrane like P-gp and MRP and excludes porting various xenobiotics (not limited to anticancer drugs)
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