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Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV-1 nucleoside reverse transcriptase

Xin Wang1, Tatsuhiko Furukawa, Takao Nitanda

  • 1Division of Human Retroviruses, Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University, Kagoshima, Japan. baba@m.kufm.kagoshima-u.ac.jp

Molecular Pharmacology
|December 19, 2002
PubMed

Insights

Breast cancer resistance protein (BCRP) confers resistance to HIV-1 nucleoside reverse transcriptase inhibitors in T cells. BCRP efflux of drug metabolites, like AZT 5'-monophosphate, drives this resistance, impacting antiviral therapy efficacy.

Area of Science:

  • Molecular Biology
  • Pharmacology
  • Virology

Background:

  • Breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding cassette transporter implicated in multidrug resistance in cancer.
  • BCRP's role in drug resistance within immune cells, particularly in the context of HIV-1 treatment, is not fully understood.

Purpose of the Study:

  • To investigate the impact of BCRP expression on cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors (NRTIs).
  • To elucidate the mechanisms underlying BCRP-mediated resistance to NRTIs in T cells.

Main Methods:

  • Established a doxorubicin-resistant cell line (MT-4/DOX 500) with high BCRP expression.
  • Assessed cellular drug accumulation, efflux, and sensitivity to various anticancer agents and anti-HIV drugs.
  • Utilized a specific BCRP inhibitor (fumitremorgin C) to confirm BCRP's role in resistance.
  • Analyzed intracellular metabolism and efflux of zidovudine (AZT).

Main Results:

  • MT-4/DOX 500 cells exhibited reduced sensitivity to doxorubicin and NRTIs like AZT and lamivudine, but not non-nucleoside reverse transcriptase inhibitors or protease inhibitors.
  • Increased ATP-dependent efflux of rhodamine 123 and reduced intracellular accumulation of doxorubicin were observed in MT-4/DOX 500 cells.
  • BCRP inhibition completely reversed the resistance to AZT and doxorubicin, indicating BCRP's critical role.
  • Resistance to AZT was attributed to increased ATP-dependent efflux of its metabolites, likely AZT 5 '-monophosphate.

Conclusions:

  • High BCRP expression in CD4+ T cells confers cellular resistance to HIV-1 NRTIs.
  • BCRP-mediated efflux of NRTI metabolites is a key mechanism driving resistance to anti-HIV therapies.
  • Targeting BCRP could potentially overcome NRTI resistance in HIV-1 treatment.

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