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Clinical Concentrations of Doxorubicin Inhibit Activity of Myocardial Membrane-associated, Calcium-independent Phospholipase A₂¹

Department of Pathology, St. Louis University School of Medicine, St. Louis, Missouri 63104 [J. M.], and Department of Physiology, Texas Tech University Health Sciences Center, Lubbock, Texas 79430 [L. M. S., A. A., N. S.]

Use of the anticancer antibiotic doxorubicin continues to be limited by its cumulative dose-related cardiotoxicity. Our study reports inhibition of myocardial intracellular calcium-independent phospholipase A₂ (iPLA₂) activity by clinically relevant concentrations of the drug. The effect was first shown in vitro using suspensions of freshly isolated rat and rabbit cardiomyocytes. Addition of 0.1–10 µM doxorubicin to these cells led to a concentration- and time-dependent inhibition of total iPLA₂, as measured using (16:0, [³H]18:1) plasmenylcholine and phosphatidylcholine substrates in the presence or absence of calcium. Subcellular fractionation into cytosolic and membrane fraction revealed that the drug selectively inhibits membrane-associated iPLA₂ activity, without altering activity of the cytosolic enzyme. Doxorubicin treatment of cells prelabeled with [H³]arachidonic acid led to a depression of baseline arachidonic acid release levels, corroborating iPLA₂ inhibition. Reducing agents blocked PLA₂ inhibition in cardiomyocyte suspensions, suggesting that the doxorubicin effect is mediated by oxidation of susceptible cysteines. In vivo experiments, in which adults rats were i.v. injected with a bolus dose of 4 mg/kg doxorubicin, confirmed in vitro findings, revealing a 2-fold decrease in membrane-associated Ca²⁺-independent iPLA₂ activity in the heart tissue of treated animals. The observed phenomenon has important implications for myocyte signaling cascades and membrane remodeling.

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