This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Swift, L. Articles by Sarvazyan, N. Search for Related Content PubMed PubMed Citation Articles by Swift, L. Articles by Sarvazyan, N.

Inhibition of Membrane-associated Calcium-independent Phospholipase A₂ as a Potential Culprit of Anthracycline Cardiotoxicity¹

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

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 A₂ (iPLA₂) 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 iPLA₂. Isolated adult rat cardiomyocytes were treated with each analogue at concentrations of 0.1–100 µM, and PLA₂ activity was assessed in cytosolic and membrane fractions using (16:0, [³H]18:1) plasmenylcholine in the absence of calcium. For all of the examined analogues, iPLA₂ inhibition was concentration and time dependent, preceded detectable changes in cell viability, and was specific to the membrane-associated enzyme. The degree of iPLA₂ 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 iPLA₂ represents the majority of myocardial PLA₂ 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 iPLA₂ inhibition may be the initial step in a chain of events leading to chronic cardiotoxicity of the anthracyclines.

This article has been cited by other articles:

				K. A. Poulsen, S. F. Pedersen, M. Kolko, and I. H. Lambert Induction of group VIA phospholipase A2 activity during in vitro ischemia in C2C12 myotubes is associated with changes in the level of its splice variants Am J Physiol Cell Physiol, November 1, 2007; 293(5): C1605 - C1615. [Abstract] [Full Text] [PDF]

				G. R. Kinsey, J. McHowat, C. S. Beckett, and R. G. Schnellmann Identification of calcium-independent phospholipase A2{gamma} in mitochondria and its role in mitochondrial oxidative stress Am J Physiol Renal Physiol, February 1, 2007; 292(2): F853 - F860. [Abstract] [Full Text] [PDF]

				L. Li, G. Takemura, Y. Li, S. Miyata, M. Esaki, H. Okada, H. Kanamori, N. C. Khai, R. Maruyama, A. Ogino, et al. Preventive Effect of Erythropoietin on Cardiac Dysfunction in Doxorubicin-Induced Cardiomyopathy Circulation, January 31, 2006; 113(4): 535 - 543. [Abstract] [Full Text] [PDF]

				J. McHowat, L. M. Swift, K. N. Crown, and N. A. Sarvazyan Changes in Phospholipid Content and Myocardial Calcium-Independent Phospholipase A2 Activity during Chronic Anthracycline Administration J. Pharmacol. Exp. Ther., November 1, 2004; 311(2): 736 - 741. [Abstract] [Full Text] [PDF]