Verapamil reverses multidrug resistance acquired by cancer cells during 
treatment with chemotherapeutic agents such as doxorubicin by inhibiting the 
function of P-glycoprotein. Verapamil has also been suggested to potentiate the 
cardiotoxicity of doxorubicin. We have recently demonstrated that selective 
inhibition of cardiac muscle gene expression is among the earliest events in 
doxorubicin cardiotoxicity. To explore the influence of verapamil on doxorubicin 
cardiotoxicity, we evaluated [14C]-doxorubicin accumulation, cardiac muscle gene 
expression by Northern blot analysis, and ultrastructural changes in cultured 
cardiomyocytes in the presence and absence of verapamil. Treatment with a 
combination of doxorubicin and verapamil for 24 h did not augment doxorubicin 
accumulation in cardiomyocytes, although substantial augmentation of doxorubicin 
accumulation by verapamil in cardiac fibroblasts was observed. Further, 
treatment with verapamil for 24 h did not augment the decrease in expression of 
muscle genes induced by doxorubicin (myosin light chain 2 slow, troponin I, M 
isoform creatine kinase). However, we found that verapamil reduced alpha-actin 
gene expression in a direct, doxorubicin-independent manner. Furthermore, the 
effect of doxorubicin plus verapamil on alpha-actin gene expression was additive 
over a wide range of doxorubicin and verapamil concentrations, resulting in a 
selective augmentation of doxorubicin-induced inhibition of gene expression for 
this single muscle protein gene. This was reflected in a substantial increase in 
cardiac myocyte damage when treatment with verapamil and doxorubicin was 
compared to treatment with doxorubicin alone by thin section electron 
microscopy. This suggests a possible mechanism by which verapamil may potentiate 
doxorubicin cardiotoxicity.