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

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

Research output: Contribution to journalArticle

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Abstract

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 (BCRPR482M). The present study demonstrated that the wild-type BCRP (BCRPWT) also conferred cellular resistance to NRTIs. MT-4 cells (a CD4+ T-cell line) highly expressing BCRPWT (MT-4/BCRP) were generated and the expression of BCRPWT 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 BCRPR482M, BCRPWT also plays an important role in cellular resistance to NRTIs.

Original languageEnglish
Pages (from-to)1363-1370
Number of pages8
JournalBiochemical Pharmacology
Volume68
Issue number7
DOIs
Publication statusPublished - 2004 Oct 1
Externally publishedYes

Fingerprint

Reverse Transcriptase Inhibitors
Nucleosides
Breast Neoplasms
T-cells
Viruses
Proteins
ATP-Binding Cassette Transporters
Zidovudine
Cytotoxicity
Metabolites
Metabolism
Antiviral Agents
HIV-1
Cells
T-Lymphocytes
Multiple Drug Resistance
Pharmaceutical Preparations
Virus Replication
Cell Line
Mutation

Keywords

  • ABC
  • ATP-binding cassette
  • AZT
  • central nervous system
  • CNS
  • HAART
  • highly active antiretroviral therapy
  • HIV-1
  • human immunodeficiency virus type 1
  • MRP
  • multidrug resistance protein
  • NRTI
  • P-glycoprotein
  • P-gp
  • PI
  • protease inhibitor
  • zidovudine

ASJC Scopus subject areas

  • Pharmacology

Cite this

Induction of cellular resistance to nucleoside reverse transcriptase inhibitors by the wild-type breast cancer resistance protein. / Wang, Xin; Nitanda, Takao; Shi, Minyi; Okamoto, Mika; Furukawa, Tatsuhiko; Sugimoto, Yoshikazu; Akiyama, Shin Ichi; Baba, Masanori.

In: Biochemical Pharmacology, Vol. 68, No. 7, 01.10.2004, p. 1363-1370.

Research output: Contribution to journalArticle

Wang, Xin ; Nitanda, Takao ; Shi, Minyi ; Okamoto, Mika ; Furukawa, Tatsuhiko ; Sugimoto, Yoshikazu ; Akiyama, Shin Ichi ; Baba, Masanori. / Induction of cellular resistance to nucleoside reverse transcriptase inhibitors by the wild-type breast cancer resistance protein. In: Biochemical Pharmacology. 2004 ; Vol. 68, No. 7. pp. 1363-1370.
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T1 - Induction of cellular resistance to nucleoside reverse transcriptase inhibitors by the wild-type breast cancer resistance protein

AU - Wang, Xin

AU - Nitanda, Takao

AU - Shi, Minyi

AU - Okamoto, Mika

AU - Furukawa, Tatsuhiko

AU - Sugimoto, Yoshikazu

AU - Akiyama, Shin Ichi

AU - Baba, Masanori

PY - 2004/10/1

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AB - 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 (BCRPR482M). The present study demonstrated that the wild-type BCRP (BCRPWT) also conferred cellular resistance to NRTIs. MT-4 cells (a CD4+ T-cell line) highly expressing BCRPWT (MT-4/BCRP) were generated and the expression of BCRPWT 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 BCRPR482M, BCRPWT also plays an important role in cellular resistance to NRTIs.

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KW - MRP

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KW - PI

KW - protease inhibitor

KW - zidovudine

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