Verapamil Potentiates 4′‐Epidoxorubicin Cytotoxicity in a Rat Hepatoma Cell Line and in a Substrain Resistant to 4′‐Epidoxorubicin

Abstract

We have examined the influence of verapamil (VP) on the in vitro effect of 4'-epidoxorubicin (Epi-A) in a rat hepatocarcinoma cell line (MHlCl) and in an Epi-A resistant substrain. A VP concentration of 500 ng/ml (1.1 mumol/l) markedly potentiated the cytotoxic effect of Epi-A in the parent line. The resistant cells grow at an Epi-A concentration of 7500 ng/ml (12.9 mumol/l). This is approximately 15-fold higher than the concentration tolerated by parental cells. In these cells VP reversed the acquired resistance to Epi-A in a concentration dependent manner; thus, a concentration in the range of 500-750 ng/ml (1.1-1.7 mumol/l) of VP restored the sensitivity to Epi-A in the resistant cells. Our results demonstrate that VP increases the sensitivity to Epi-A in hepatocarcinoma cells never exposed to this drug, as well as in hepatocarcinoma cells with acquired Epi-A resistance.