Inhibition by adriamycin of calmodulin-sensitive and phospholipid-sensitive calcium-dependent phosphorylation of endogenous proteins from heart.
Adriamycin, a lipid-interacting anti-cancer agent, was found to inhibit phospholipid-sensitive Ca2+-dependent phosphorylation of endogenous proteins from the cytosol of the guinea-pig heart. The drug, unexpectedly, also inhibited phosphorylation of separate endogenous proteins in the cardiac cytosol and membranes catalysed by the calmodulin-sensitive species of Ca2+-dependent protein kinase. In both phosphorylation systems, the inhibition by adriamycin was reversed by either phospholipid (phosphatidylserine or cardiolipin) or calmodulin respectively. Adriamycin also inhibited phosphorylation of histone (exogenous protein) catalysed by purified cardiac phospholipid-sensitive Ca2+-dependent protein kinase, but not that by cyclic AMP-dependent and cyclic GMP-dependent protein kinases. It appears that 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.
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000494:pharmacology*; D002147:Calmodulin / Q000494:pharmacology*; D003864:Depression, Chemical; D004317:Doxorubicin / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010743:Phospholipids / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D011506:Proteins / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D002147:Calmodulin; D010743:Phospholipids; D047428:Protein Kinase Inhibitors; D011506:Proteins; D004317:Doxorubicin; D002118:Calcium