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 language | English |
|---|---|
| Pages (from-to) | 1363-1370 |
| Number of pages | 8 |
| Journal | Biochemical Pharmacology |
| Volume | 68 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 2004 Oct 1 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
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
Y1 - 2004/10/1
N2 - 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.
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.
KW - ABC
KW - ATP-binding cassette
KW - AZT
KW - central nervous system
KW - CNS
KW - HAART
KW - highly active antiretroviral therapy
KW - HIV-1
KW - human immunodeficiency virus type 1
KW - MRP
KW - multidrug resistance protein
KW - NRTI
KW - P-glycoprotein
KW - P-gp
KW - PI
KW - protease inhibitor
KW - zidovudine
UR - http://www.scopus.com/inward/record.url?scp=4444383451&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4444383451&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2004.05.052
DO - 10.1016/j.bcp.2004.05.052
M3 - Article
C2 - 15345326
AN - SCOPUS:4444383451
VL - 68
SP - 1363
EP - 1370
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 7
ER -