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Vol. 63, Issue 1, 65-72, January 2003

Breast Cancer Resistance Protein (BCRP/ABCG2) Induces Cellular Resistance to HIV-1 Nucleoside Reverse Transcriptase Inhibitors

Xin Wang, Tatsuhiko Furukawa, Takao Nitanda, Mika Okamoto, Yoshikazu Sugimoto, Shin-Ichi Akiyama, and Masanori Baba

Division of Human Retroviruses, Center for Chronic Viral Diseases (X.W., T.N., M.O., M.B.), and Department of Cancer Chemotherapy, Institute for Cancer Research (T.F., S.A.), Faculty of Medicine, Kagoshima University, Kagoshima, Japan; and Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan (Y.S.)

Breast cancer resistance protein (BCRP/ABCG2) is a novel member of ATP- binding cassette transporters, which induce multidrug resistance in cancer cells. We found that a high level of BCRP expression in CD4+ T cells conferred cellular resistance to human immunodeficiency virus type-1 (HIV-1) nucleoside reverse transcriptase inhibitors. The cell line MT-4/DOX500 was established through the long-term culture of MT-4 cells in the presence of doxorubicin (DOX) and had reduced sensitivity to not only DOX but also zidovudine (AZT). MT-4/DOX500 cells showed reduced intracellular accumulation and retention of DOX and increased ATP-dependent rhodamine 123 efflux. The cells were also resistant to several anticancer agents such as mitoxantrone, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin, and 7-ethyl-10-hydroxycamptothecin. AZT was 7.5-fold less inhibitory to HIV-1 replication in MT-4/DOX500 cells than in MT-4 cells. Furthermore, the anti-HIV-1 activity of lamivudine was severely impaired in MT-4/DOX500 cells. In contrast, the antiviral activity of non-nucleoside reverse transcriptase inhibitors and protease inhibitors was not affected in the cells. MT-4/DOX500 cells expressed glycosylated BCRP but not P-glycoprotein (ABCB1), multidrug resistance protein 1, 2, or 4 (ABCC1, -2, or -4), or lung resistance-related protein. In addition, the BCRP-specific inhibitor fumitremorgin C completely abolished the resistance of MT-4/DOX500 cells to AZT as well as to DOX. An analysis for intracellular metabolism of AZT suggests that the resistance is attributed to the increase of ATP-dependent efflux of its metabolites, presumably AZT 5'-monophosphate, in MT-4/DOX500 cells.

Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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