Document Detail

Induction of cellular resistance to nucleoside reverse transcriptase inhibitors by the wild-type breast cancer resistance protein.
MedLine Citation:
PMID:  15345326     Owner:  NLM     Status:  MEDLINE    
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.
Xin Wang; Takao Nitanda; Minyi Shi; Mika Okamoto; Tatsuhiko Furukawa; Yoshikazu Sugimoto; Shin-ichi Akiyama; Masanori Baba
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  68     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2004 Oct 
Date Detail:
Created Date:  2004-09-03     Completed Date:  2004-11-03     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1363-70     Citation Subset:  IM    
Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.
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MeSH Terms
ATP-Binding Cassette Transporters / antagonists & inhibitors,  physiology*
Anti-HIV Agents / pharmacokinetics,  pharmacology*
Antineoplastic Agents, Phytogenic / pharmacology*
CD4-Positive T-Lymphocytes / drug effects*,  metabolism
Cell Survival / drug effects
Cells, Cultured
Doxorubicin / pharmacology
Drug Resistance, Multiple / physiology*
Drug Resistance, Neoplasm
HIV-1 / drug effects
Indoles / pharmacology
Neoplasm Proteins / antagonists & inhibitors,  physiology*
Reverse Transcriptase Inhibitors / pharmacology*
Zidovudine / pharmacokinetics,  pharmacology
Reg. No./Substance:
0/ABCG2 protein, human; 0/ATP-Binding Cassette Transporters; 0/Anti-HIV Agents; 0/Antineoplastic Agents, Phytogenic; 0/Indoles; 0/Neoplasm Proteins; 0/Reverse Transcriptase Inhibitors; 23214-92-8/Doxorubicin; 30516-87-1/Zidovudine; 55387-45-6/tryptoquivaline

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