Published in:
01-09-2011 | Original Article
Over-expression of MDR1 in amrubicinol-resistant lung cancer cells
Authors:
Osamu Takakuwa, Tetsuya Oguri, Hiroaki Ozasa, Takehiro Uemura, Daishi Kasai, Mikinori Miyazaki, Ken Maeno, Shigeki Sato
Published in:
Cancer Chemotherapy and Pharmacology
|
Issue 3/2011
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Abstract
Purpose
Amrubicin, a totally synthetic 9-aminoanthracycline anticancer drug, has shown promising activity for lung cancer, but little is known about the mechanism of resistance for this agent. This study was aimed to clarify the role of P-glycoprotein (P-gp) in amrubicinol, an active metabolite of amrubicin, resistance in lung cancer cells.
Methods
Amrubicinol-resistant cell line PC-6/AMR-OH was developed by continuously exposing the small-cell lung cancer cell line PC-6 to amrubicinol. Gene expression level of MDR1, which encodes P-gp, and intracellular accumulation of amrubicinol were evaluated by PC-6 and PC-6/AMR-OH cells. The involvement of MDR1 in amrubicinol resistance was evaluated by treatment with P-gp inhibitor verapamil and small interfering RNA (siRNA) against MDR1. Also, expression levels and single-nucleotide polymorphisms (SNPs) of MDR1 in 22 lung cancer cell lines were examined, and the relationships between these factors and sensitivity to amrubicinol were evaluated.
Results
The MDR1 gene was increased approximately 4,500-fold in PC-6/AMR-OH cells compared with PC-6 cells, and intracellular accumulation of amrubicinol in PC-6/AMR-OH cells was decreased to about 15 percent of that in PC-6 cells. Treatment with verapamil and siRNA against MDR1 significantly increased the sensitivity to amrubicinol in PC-6/AMR-OH cells with increased cellular accumulation of amrubicinol. Meanwhile, neither MDR1 gene expression levels nor SNPs of the gene were associated with amrubicinol sensitivity.
Conclusions
Results of this study indicate that increased MDR1 expression and P-gp activity confer acquired resistance to amrubicinol. In contrast, neither expression level nor SNPs of MDR1 are likely to be predictive markers for amrubicin activity.