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Over-expression of MDR1 in amrubicinol-resistant lung cancer cells

Osamu Takakuwa1, Tetsuya Oguri, Hiroaki Ozasa

  • 1Department of Medical Oncology and Immunology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.

Cancer Chemotherapy and Pharmacology
|December 4, 2010
PubMed
Abstract

Insights

Increased P-glycoprotein (P-gp) activity causes resistance to amrubicinol, an active metabolite of amrubicin, in lung cancer cells. This resistance is linked to higher MDR1 gene expression, not its levels or SNPs.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Amrubicinol is a promising anticancer drug for lung cancer.
  • The mechanisms of amrubicinol resistance are not fully understood.
  • P-glycoprotein (P-gp) is a key mediator of multidrug resistance.

Purpose of the Study:

  • To investigate the role of P-glycoprotein (P-gp) in amrubicinol resistance in lung cancer cells.
  • To determine if MDR1 gene expression or its single-nucleotide polymorphisms (SNPs) correlate with amrubicinol sensitivity.

Main Methods:

  • Developed an amrubicinol-resistant small-cell lung cancer cell line (PC-6/AMR-OH).
  • Assessed MDR1 gene expression and intracellular amrubicinol accumulation in resistant and sensitive cells.
  • Utilized P-gp inhibitor verapamil and MDR1-targeting siRNA to evaluate drug sensitivity.

Main Results:

  • PC-6/AMR-OH cells showed a 4,500-fold increase in MDR1 gene expression.
  • Intracellular amrubicinol accumulation decreased to 15% in resistant cells.
  • Verapamil and MDR1 siRNA treatments restored amrubicinol sensitivity and cellular accumulation.

Conclusions:

  • Increased MDR1 expression and P-gp activity lead to acquired resistance to amrubicinol.
  • MDR1 expression levels and SNPs are not reliable predictors of amrubicinol efficacy.

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