Induction of cellular resistance to nucleoside reverse transcriptase inhibitors by the wild-type breast cancer resistance protein

Biochem Pharmacol. 2004 Oct 1;68(7):1363-70. doi: 10.1016/j.bcp.2004.05.052.


Breast cancer resistance protein (BCRP/ABCG2) is a novel member of ATP-binding cassette transporters, which induce multidrug resistance in cancer cells. We previously reported that a high level of BCRP expression in CD4(+) T cells conferred cellular resistance to nucleoside reverse transcriptase inhibitors (NRTIs) of human immunodeficiency virus type 1 (HIV-1). However, this BCRP was found to have a mutation of Arg to Met at position 482 (BCRP(R482M)). The present study demonstrated that the wild-type BCRP (BCRP(WT)) also conferred cellular resistance to NRTIs. MT-4 cells (a CD4(+) T-cell line) highly expressing BCRP(WT) (MT-4/BCRP) were generated and the expression of BCRP(WT) was confirmed by genotypic and phenotypic analyses. Compared to the parental MT-4 cells, MT-4/BCRP cells displayed resistance to zidovudine (AZT) in terms of antiviral activity as well as drug cytotoxicity. In addition, other NRTIs were also less inhibitory to HIV-1 replication in MT-4/BCRP cells than in MT-4 cells. Significant reduction of intracellular AZT accumulation was observed in MT-4/BCRP cells. An analysis for intracellular metabolism of AZT suggested that the resistance was attributed to the increased efflux of AZT and its metabolites in MT-4/BCRP cells. Furthermore, the BCRP-specific inhibitor fumitremorgin C completely restored the reduction of AZT in MT-4/BCRP cells. These results indicate that, like BCRP(R482M), BCRP(WT) also plays an important role in cellular resistance to NRTIs.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / physiology*
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple / physiology*
  • Drug Resistance, Neoplasm
  • HIV-1 / drug effects
  • Humans
  • Indoles / pharmacology
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / physiology*
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Zidovudine / pharmacokinetics
  • Zidovudine / pharmacology


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Anti-HIV Agents
  • Antineoplastic Agents, Phytogenic
  • Indoles
  • Neoplasm Proteins
  • Reverse Transcriptase Inhibitors
  • Zidovudine
  • Doxorubicin
  • tryptoquivaline