EFFECT OF VERAPAMIL ON DOXORUBICIN CARDIOTOXICITY - ALTERED MUSCLE GENE-EXPRESSION IN CULTURED NEONATAL RAT CARDIOMYOCYTES

Verapamil reverses multidrug resistance acquired by cancer cells durin g treatment with chemotherapeutic agents such as doxorubicin by inhibi ting the function of P-glycoprotein. Verapamil has also been suggested to potentiate the cardiotoxicity of doxorubicin. We have recently dem onstrated 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 evaluate d [C-14]-doxorubicin accumulation, cardiac muscle gene expression by N orthern blot analysis, and ultrastructural changes in cultured cardiom yocytes in the presence and absence of verapamil. Treatment with a com bination of doxorubicin and verapamil for 24 h did not augment doxorub icin accumulation in cardiomyocytes, although substantial augmentation of doxorubicin accumulation by verapamil in cardiac fibroblasts was o bserved. Further, treatment with verapamil for 24 h did not augment th e decrease in expression of muscle genes induced by doxorubicin (myosi n light chain 2 slow, troponin 1, M isoform creatine kinase). However, we found that verapamil reduced alpha-actin gene expression in a dire ct, doxorubicin-independent manner. Furthermore, the effect of doxorub icin plus verapamil on a-actin gene expression was additive over a wid e range of doxorubicin and verapamil concentrations, resulting in a se lective augmentation of doxorubicin-induced inhibition of gene express ion for this single muscle protein gene. This was reflected in a subst antial increase in cardiac myocyte damage when treatment with verapami l and doxorubicin was compared to treatment with doxorubicin alone by thin section electron microscopy. This suggests a possible mechanism b y which verapamil may potentiate doxorubicin cardiotoxicity.