Inhibition of membrane-associated calcium-independent phospholipase A2 as a potential culprit of anthracycline cardiotoxicity.

Administration of anthracyclines, a family of highly effective anticancer drugs, is associated with a cumulative dose-related cardiomyopathy, the etiology of which remains poorly understood. We have discovered that administration of the anthracyclines leads to a marked inhibition of membrane-associated calcium-independent phospholipase A(2) (iPLA(2)) both in vitro and in vivo. To elucidate the clinical relevance of this effect and to correlate it with known cardiotoxicity of the individual anthracyclines, we have compared four anthracycline analogues: doxorubicin, daunorubicin, idarubicin, and epirubicin for their ability to inhibit iPLA(2). Isolated adult rat cardiomyocytes were treated with each analogue at concentrations of 0.1-100 micro M, and PLA(2) activity was assessed in cytosolic and membrane fractions using (16:0, [(3)H]18:1) plasmenylcholine in the absence of calcium. For all of the examined analogues, iPLA(2) inhibition was concentration and time dependent, preceded detectable changes in cell viability, and was specific to the membrane-associated enzyme. The degree of iPLA(2) inhibition by equimolar concentrations of epirubicin and idarubicin was significantly less than that of doxorubicin or daunorubicin, which correlates with the reported in vivo cardiotoxicity of these drugs. Because membrane iPLA(2) represents the majority of myocardial PLA(2) activity, its inhibition by anthracyclines would critically impair the ability of cardiomyocytes to repair oxidized phospholipids. Indeed, anthracycline-pretreated myocytes become more susceptible to the low-level oxidative stress imposed by repetitive additions of tert-butyl peroxide. The results suggest that iPLA(2) inhibition may be the initial step in a chain of events leading to chronic cardiotoxicity of the anthracyclines.