Related Experiment Videos
Effects of carvedilol on MDR1-mediated multidrug resistance: comparison with verapamil
Mikio Kakumoto1, Toshiyuki Sakaeda, Kohji Takara
1Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017.
Abstract:
The reversing effects of carvedilol and other beta-adrenoceptor antagonists on multidrug resistance (MDR) were assessed in HeLa cells and the MDR1-overexpressing derivative Hvr100-6 cells, established by stepwise increases of vinblastine concentration in the culture medium. The inhibitory effects on the transcellular transport and intracellular accumulation of [3H]vinblastine and [3H]daunorubicin were also assessed using LLC-GA5-COL150 cell monolayers, established by transfection of human MDR1 cDNA into porcine kidney epithelial LLC-PK1 cells. The cytotoxic effects of vinblastine, paclitaxel, doxorubicin and daunorubicin in Hvr100-6 were reversed 1.4- to 7.1-fold by carvedilol at the realistic clinical concentration of 1 microM, whereas other beta-adrenoceptor antagonists had weaker or no such effects. Transport experiments using LLC-GA5-COL150 cell monolayers demonstrated that this effect of carvedilol was due to the inhibition of MDR1-mediated transport of vinblastine, paclitaxel, doxorubicin and daunorubicin. These MDR1-mediated reversing effects of carvedilol were similar to those of 1 microM verapamil, suggesting that carvedilol could be a candidate modulator of MDR in clinical use. Since other beta-adrenoceptor antagonists had no inhibitory effect on transport, the effects of carvedilol were not related to beta-adrenoceptors and might have been due to antioxidant activity.
Insights
Carvedilol reverses multidrug resistance (MDR) by inhibiting the MDR1 transporter, unlike other beta-blockers. This suggests carvedilol
Area of Science:
- Pharmacology
- Cell Biology
- Cancer Research
Background:
- Multidrug resistance (MDR) limits chemotherapy efficacy.
- MDR1 P-glycoprotein is a key efflux pump in MDR.
- Beta-adrenoceptor antagonists are commonly used drugs.
Purpose of the Study:
- To investigate the MDR-reversing effects of carvedilol and other beta-blockers.
- To determine if carvedilol inhibits MDR1-mediated drug transport.
- To explore the potential of carvedilol as an MDR modulator.
Main Methods:
- Cell culture: HeLa, MDR1-overexpressing Hvr100-6, and LLC-GA5-COL150 cells.
- Cytotoxicity assays with vinblastine, paclitaxel, doxorubicin, and daunorubicin.
- Transport assays using radiolabeled drugs to assess transcellular transport and intracellular accumulation.
Main Results:
- Carvedilol reversed MDR 1.4- to 7.1-fold at 1 microM in Hvr100-6 cells.
- Other beta-blockers showed weaker or no MDR-reversing effects.
- Carvedilol inhibited MDR1-mediated transport of multiple chemotherapy drugs, similar to verapamil.
- Carvedilol's effect was independent of beta-adrenoceptors, possibly due to antioxidant activity.
Conclusions:
- Carvedilol effectively reverses MDR by inhibiting the MDR1 transporter.
- Carvedilol shows potential as a clinical modulator of MDR.
- The MDR-modulating effects of carvedilol are likely due to mechanisms beyond beta-adrenoceptor antagonism, such as antioxidant properties.