Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters
Vlasta Němcová‐FürstováDana KopperováKamila BalušíkováMarie EhrlichováVeronika BrynychováRadka VáclavíkováPetr DanielPavel SoučekJan Kovář
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ATP-binding cassette (ABC) genes play a role in the resistance of malignant cells to anticancer agents. The ABC gene products, including ABCB1 (P-glycoprotein) and ABCG2 (breast cancer-resistance protein [BCRP], mitoxantrone-resistance protein [MXR], or ABC transporter in placenta [ABCP]), are also known to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. Naturally occurring variants in ABC transporter genes have been identified that might affect the function and expression of the protein. This review focuses on recent advances in the pharmacogenetics of the ABC transporters ABCB1 and ABCG2, and discusses potential implications of genetic variants for the chemotherapeutic treatment of cancer.
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Adenosine triphosphate-binding cassette (ABC) transporters, such as P-glycoprotein (Pgp, ABCB1), breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance-associated proteins (MRPs) are expressed in high concentrations at various physiological barriers (e.g. blood-brain barrier, blood-testis barrier, blood-tumor barrier), where they impede the tissue accumulation of various drugs by active efflux transport. Changes in ABC transporter expression and function are thought to be implicated in various diseases, such as cancer, epilepsy, Alzheimers and Parkinsons disease. The availability of a non-invasive imaging method which allows for measuring ABC transporter function or expression in vivo would be of great clinical use in that it could facilitate the identification of those patients that would benefit from treatment with ABC transporter modulating drugs. To date three different kinds of imaging probes have been described to measure ABC transporters in vivo: i) radiolabelled transporter substrates ii) radiolabelled transporter inhibitors and iii) radiolabelled prodrugs which are enzymatically converted into transporter substrates in the organ of interest (e.g. brain). The design of new imaging probes to visualize efflux transporters is inter alia complicated by the overlapping substrate recognition pattern of different ABC transporter types. The present article will describe currently available ABC transporter radiotracers for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) and critically discuss strengths and limitations of individual probes and their potential clinical applications. Keywords: ABC transporter, blood-brain barrier, breast cancer resistance protein, multidrug resistance-associated protein, P-glycoprotein, Positron emission tomography, single-photon emission computed tomography, tariquidar (XR9576), zosuquidar (LY335979), phosphatidylcholine translocase
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ATP binding cassette (ABC) transporters are involved in drug absorption, distribution and elimination. They also mediate multidrug resistance in cancer cells. Isoflavones, such as genistein (GNT), belong to a class of naturally-occurring compounds found at high concentrations in commonly consumed soya based-foods and dietary supplements. GNT and its metabolites interact with ABC transporters as substrates, inhibitors and/or modulators of their expression. This review compiles information about regulation of ABC transporters by GNT with special emphasis on the three major groups of ABC transporters involved in excretion of endo- and xenobiotics as follows: Pglycoprotein (MDR1, ABCB1), a group of multidrug resistance associated proteins (MRPs, ABCC subfamily) and ABCG2 (BCRP), an ABC half-transporter. The impact of these regulations on potential GNT-drug interactions is further considered.
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P-Glycoprotein (P-gp, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2) are the three major ABC transport proteins conferring resistance to many structurally diverse anticancer agents, leading to the phenomenon called multidrug resistance (MDR). Much effort has been put into the development of clinically useful compounds to reverse MDR. Broad-spectrum inhibitors of ABC transport proteins can be of great use in cancers that simultaneously coexpress two or three transporters. In this work, we continued our effort to generate new, potent, nontoxic, and multiply effective inhibitors of the three major ABC transporters. The best compound was active in a very low micromolar concentration range against all three transporters and restored sensitivity toward daunorubicin (P-gp and MRP1) and SN-38 (BCRP) in A2780/ADR (P-gp), H69AR (MRP1), and MDCK II BCRP (BCRP) cells. Additionally, the compound is a noncompetitive inhibitor of daunorubicin (MRP1), calcein AM (P-gp), and pheophorbide A (BCRP) transport.
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A significant impediment to the success of cancer chemotherapy is multidrug resistance (MDR)and this could be attributable to concomitance of multiple intricate mechanisms.Overexpression or functional abnormality of membrane drug transport proteins of ATP-binding cassette(ABC)family which results in an increased drug efflux,could be one of the main mechanisms.Accumulative evidence shows that P-glycoprotein(P-gp),Muhidrug resistance-associated proteins(MRPs)and breast cancer resistance protein(BCRP),identified in last three decades,confer resistance to multiple chemotherapeu- tic agents when overexpressed in human tumors.This review will address the structure and function of drug transporters in ABC family and focus on the research advancement on the mechanism of tumors multidrug resistance mediated by ABC transporters family and the development of their inhibitors.
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The recent identification of drug-metabolizing enzymes cytochrome P450 (CYP) in the human blood-brain barrier (BBB) raises the question of whether these enzymes act in concert with ATP-binding cassette (ABC) transporters to limit the brain distributions of drugs. We recently demonstrated several CYP genes in freshly isolated human brain microvessels; the main isoforms expressed were CYP1B1 and CYP2U1. Many studies using different experimental approaches have revealed that P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP, ABCG2) and the multidrug resistance-associated protein 4 (MRP4, ABCC4) are the main ABC transporters in the human BBB. The first part of this review covers recent studies on the expression, regulation and function of CYP450 and ABC transporters in the rodent and human BBBs. The second part focuses on the possible interplay between some CYPs and certain ABC transporters at the BBB, which makes it a determining element of brain drug concentrations and thus of the effects of centrally acting drugs. Keywords: ATP-binding cassette transporters, blood-brain barrier, cytochromes P450, expression, interplay, regulation, brain microvascular endothelial cells (BMECs), first-pass effect, abluminal plasma membranes, CAR
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