Sensitization Effects of Repurposed Blood Pressure-regulating Drugs on Drug-resistant Cancer Cells

Abstract

Background/Aim: We investigated drugs that could sensitize KBV20C cancer cells resistant to eribulin or vincristine (VIC) treatment and assessed their associated mechanisms of action. Materials and Methods: Such cancer cells were known to overexpress P-glycoprotein (P-gp). Considering that reserpine (P-gp inhibitor) plays a regulatory role in patients with high blood pressure, we investigated the effect of low doses of 27 blood pressure-regulating drugs on VIC-resistant KBV20C cells. This was done to identify drugs that could be repurposed for sensitizing antimitotic drug-resistant KBV20C cells at relatively low doses. Fluorescence-activated cell sorting (FACS), annexin V analyses, rhodamine uptake tests and western-blot analysis were performed to further investigate the mechanism of action of such drugs. Results: We found that co-treatment with amiodarone, nicardipine, carvedilol, or vardenafil at low doses could highly sensitize KBV20C cells treated with eribulin or VIC. These drugs reduced cellular viability, increased G(2) arrest and up-regulated apoptosis when co-administered with eribulin or VIC. Considering that they sensitize with either co-treatment of eribulin or VIC, we assumed that they can be combined with other antimitotic drugs to sensitize the resistant cancer cells. Through detailed quantitative analysis, we found that eribulin with amiodarone had a higher sensitization effect than eribulin with nicardipine or eribulin with carvedilol. We found that reserpine had the highest P-gp-inhibitory activity, indicating that eribulin or VIC-reserpine sensitization involves the P-gp inhibitory effects of reserpine. However, we found that amiodarone, nicardipine, carvedilol and vardenafil had very low P-gp inhibitory activity. Moreover, we found that cells co-treated with VIC-carvedilol down-regulated expression of pERK. Conclusion: Highly antimitotic drug-resistant KBV20C cells can be sensitized by co-treatment with the repurposed blood pressure-regulating drugs amiodarone, nicardipine, carvedilol or vardenafil. These findings indicate that the repurposed blood pressure-regulating drugs may potentially be used in drug-resistant cancer patients without any toxic effects due to P-gp inhibition.