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Effect of Verapamil on Doxorubicin Cardiotoxicity: Altered Muscle Gene Expression in Cultured Neonatal Rat Cardiomyocytes¹

Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, and the Palo Alto Veterans Affairs Medical Center, Palo Alto, California 94304 [H. A., S. V. T., F. M. T.]; Department of Tumor Biology, Institute of Biochemistry and Cell Biology, Syntex Research, Palo Alto, California 94304 [N. A. B., D. L. S.]; and Department of Pathology, Stanford University School of Medicine, Stanford, California 94305 [M. E. B.]

³ To whom requests for reprints should be addressed, at Comprehensive Cancer Center of Wake Forest University, Bowman Gray School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157.

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 -actin gene expression in a direct, doxorubicin-independent manner. Furthermore, the effect of doxorubicin plus verapamil on a-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.

¹ This work was supported by a grant from the American Cancer Society (PDT-439), and gifts from the Smith and Ruehl families.

² Present address: Cardiology Division, Tokyo Medical and Dental University, Toyko 113, Japan.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/17/93. Accepted 7/28/93.

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