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Effects of 12 Ca2+ antagonists on multidrug resistance, MDR1-mediated transport and MDR1 mRNA expression
Kohji Takara1, Toshiyuki Sakaeda, Yusuke Tanigawara
1Department of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-Cho, Misasagi, Yamashina-Ku, Kyoto, 607-8414, Japan.
Abstract:
The effects of 12 Ca(2+) antagonists on MDR1 were examined by two independent models: the inhibitory effect on MDR1-mediated transport of [(3)H]digoxin using MDR1-overexpressing LLC-GA5-COL150 cell monolayers and the reversal effect on cytotoxicity of vinblastine or paclitaxel using MDR1-overexpressing Hvr100-6 cells. The inhibitory effects on [(3)H]digoxin transport were assessed as the 50% inhibitory concentration during 4 h exposure, and the values were the lowest for nicardipine (4.54 microM), manidipine (4.65 microM) and benidipine (4.96 microM), followed by bepridil (10.6 microM), barnidipine (12.6 microM), efonidipine (13.0 microM), verapamil (13.2 microM) and nilvadipine (18.0 microM). The reversal effect on cytotoxicity was assessed by the 50% growth inhibitory concentration after 3 days exposure, and the resistance to vinblastine or paclitaxel in Hvr100-6 cells was reversed by manidipine, verapamil, benidipine, barnidipine, and nicardipine, in that order. Bepridil, barnidipine, efonidipine, verapamil and nilvadipine showed similar inhibitory effects on [(3)H]digoxin transport, but barnidipine and verapamil showed a stronger effect in reversal of cytotoxicity. Real-time quantitative RT-PCR assay indicated a decrease in MDR1 mRNA expression by barnidipine and verapamil. It is concluded that Ca(2+) antagonists cannot only be direct inhibitors of MDR1 but that some may at the same time act as inhibitors of expression of MDR1 via down-regulation of MDR1 mRNA.
Insights
Twelve calcium (Ca2+) antagonists were evaluated for their effects on multidrug resistance 1 (MDR1). Some Ca2+ antagonists directly inhibit MDR1, while others also decrease MDR1 mRNA expression, suggesting dual action.
Area of Science:
- Pharmacology
- Molecular Biology
- Cancer Research
Background:
- Multidrug resistance 1 (MDR1) is a key factor in chemotherapy failure.
- Calcium (Ca2+) antagonists are widely used drugs with potential off-target effects.
- Understanding MDR1 modulation by Ca2+ antagonists is crucial for optimizing cancer therapy.
Purpose of the Study:
- To investigate the inhibitory and reversal effects of 12 Ca2+ antagonists on MDR1.
- To determine if Ca2+ antagonists affect MDR1 expression at the mRNA level.
Main Methods:
- Assessed MDR1-mediated digoxin transport in MDR1-overexpressing cells.
- Evaluated reversal of vinblastine/paclitaxel cytotoxicity in MDR1-overexpressing cells.
- Quantified MDR1 mRNA expression using real-time quantitative RT-PCR.
Main Results:
- Nicardipine, manidipine, and benidipine showed the lowest inhibitory concentrations on digoxin transport.
- Manidipine, verapamil, benidipine, barnidipine, and nicardipine reversed drug resistance.
- Barnidipine and verapamil demonstrated stronger reversal effects and decreased MDR1 mRNA expression.
Conclusions:
- Ca2+ antagonists can directly inhibit MDR1 activity.
- Certain Ca2+ antagonists, like barnidipine and verapamil, also down-regulate MDR1 gene expression.
- These findings suggest a dual mechanism for some Ca2+ antagonists in overcoming multidrug resistance.