Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

Abstract

Observations of functional adenosine triphosphate (ATP)-dependent drug efflux in certain multidrug-resistant cancer cell lines without overexpression of P-glycoprotein or multidrug resistance protein (MRP) family members suggested the existence of another ATP-binding cassette (ABC) transporter capable of causing cancer drug resistance. In one such cell line (MCF-7/AdrVp), the overexpression of a novel member of the G subfamily of ABC transporters was found. The new transporter was termed the breast cancer resistance protein (BCRP), because of its identification in MCF-7 human breast carcinoma cells. BCRP is a 655 amino-acid polypeptide, formally designated as ABCG2. Like all members of the ABC G (white) subfamily, BCRP is a half transporter. Transfection and enforced overexpression of BCRP in drug-sensitive MCF-7 or MDA-MB-231 cells recapitulates the drug-resistance phenotype of MCF-7/AdrVp cells, consistent with current evidence suggesting that functional BCRP is a homodimer. BCRP maps to chromosome 4q22, downstream from a TATA-less promoter. The spectrum of anticancer drugs effluxed by BCRP includes mitoxantrone, camptothecin-derived and indolocarbazole topoisomerase I inhibitors, methotrexate, flavopiridol, and quinazoline ErbB1 inhibitors. Transport of anthracyclines is variable and appears to depend on the presence of a BCRP mutation at codon 482. Potent and specific inhibitors of BCRP are now being developed, opening the door to clinical applications of BCRP inhibition. Owing to tissue localization in the placenta, bile canaliculi, colon, small bowel, and brain microvessel endothelium, BCRP may play a role in protecting the organism from potentially harmful xenobiotics. BCRP expression has also been demonstrated in pluripotential 'side population' stem cells, responsible for the characteristic ability of these cells to exclude Hoechst 33342 dye, and possibly for the maintenance of the stem cell phenotype. Studies are emerging on the role of BCRP expression in drug resistance in clinical cancers. More prospective studies are needed, preferably combining BCRP protein or mRNA quantification with functional assays, in order to determine the contribution of BCRP to drug resistance in human cancers.

MDR1 in immunity: friend or foe?

“…1 We find some endogenous compounds like amyloid-β, steroids and platelet-activating factor (PAF) 5–7,14 but mainly a very large number of therapeutic drugs (Table 1). 15 However, two other important ABC transporters, Breast Cancer Resistance Protein 1 (BCRP-1) 16 and Multidrug Resistance Protein 1 (MRP-1), 17 have also been implicated in chemotherapeutic resistance with a partially shared substrate specificity with MDR1 (Table 1). Polymorphisms of ABCB1 can also modify the efflux capacities of various substrates.…”

MDR1 and BCRP Transporter-Mediated Drug-Drug Interaction between Rilpivirine and Abacavir and Effect on Intestinal Absorption

“…P-glycoprotein (ABCB1/MDR1) (10,11), breast cancer resistance protein (ABCG2/ BCRP) (12), and multidrug resistance-associated protein 2 (ABCC2/MRP2) (13) are well-described members of ATP-binding cassette (ABC) drug transporters that are functionally expressed in the small intestine, blood-tissue barriers, and excretory organs (14)(15)(16)(17). Together with organic cation transporters (OCTs; SLC22A) of the SLC super-family, they largely influence intestinal absorption and diminish distribution of drugs into sensitive body tissues (14,15,17,18).…”

Modifying the Sugar Moieties of Daunorubicin Overcomes P-gp-Mediated Multidrug Resistance

“…The 3'-amino group in the sugar may plays a role for P-gp recognition [24,25], but it has also been suggested [18] that the amino group may stabilize intercalation of DNA. When the 3'-NH 2 of doxorubicin was replaced with a 3'-OH or 3'-N-methylation, the resulting compounds partially reversed drug resistance [32][33][34][35][36][37][38][39][40], but were slightly less cytotoxic. Furthermore, these daunorubicin analogs in our study are only slightly modified in their structures.…”