Swift Luther, McHowat Jane, Sarvazyan Narine
Department of Physiology, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA.
Cancer Res. 2003 Sep 15;63(18):5992-8.
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.
蒽环类药物是一类高效抗癌药物，其使用与累积剂量相关的心肌病有关，但其病因仍知之甚少。我们发现，蒽环类药物的使用在体外和体内均会导致膜相关的钙非依赖性磷脂酶A2（iPLA2）受到显著抑制。为了阐明这种效应的临床相关性，并将其与各蒽环类药物已知的心脏毒性相关联，我们比较了四种蒽环类类似物：阿霉素、柔红霉素、伊达比星和表柔比星抑制iPLA2的能力。将分离的成年大鼠心肌细胞用每种类似物以0.1 - 100 μM的浓度处理，并在无钙条件下使用（16:0，[(3)H]18:1）缩醛磷脂胆碱评估胞质和膜部分的PLA2活性。对于所有检测的类似物，iPLA2抑制呈浓度和时间依赖性，先于细胞活力的可检测变化，且对膜相关酶具有特异性。等摩尔浓度的表柔比星和伊达比星对iPLA2的抑制程度明显低于阿霉素或柔红霉素，这与这些药物在体内的心脏毒性报道相关。由于膜iPLA2代表了心肌PLA2活性的大部分，蒽环类药物对其的抑制会严重损害心肌细胞修复氧化磷脂的能力。事实上，经蒽环类药物预处理的心肌细胞对重复添加叔丁基过氧化物所施加的低水平氧化应激变得更加敏感。结果表明，iPLA2抑制可能是导致蒽环类药物慢性心脏毒性的一系列事件的初始步骤。
