Inhibition by adriamycin of calmodulin-sensitive and phospholipid-sensitive calcium-dependent phosphorylation of endogenous proteins from heart

Abstract

Adriamycin, a lipid-interacting anti-cancer agent, inhibits phospholipid-sensitive Ca2+-dependent phosphorylation of endogenous proteins from the cytosol of the guinea pig heart. The drug inhibited phosphorylation of separate endogenous proteins in the cardiac cytosol and membranes catalyzed by the calmodulin-sensitive species of Ca2+-dependent protein kinase. In both phosphorylation systems, the inhibition by adriamycin was reversed by phospholipid (phosphatidylserine or cardiolipin) or calmodulin, respectively. Adriamycin inhibited phosphorylation of histone (exogenous protein) catalyzed by purified cardiac phospholipid-sensitive Ca2+-dependent protein kinase, but not that by cAMP-dependent and cyclic GMP-dependent protein kinases. Ca2+-dependent protein phosphorylation systems, regulated either by phospholipid or calmodulin, may represent hitherto unrecognized sites of action of adriamycin. It remains to be seen whether inhibition by adriamycin of these systems is related to the severe cardiotoxicity, the major adverse effect of the drug that limits its clinical usefulness.