Doxorubicin-induced platelet cytotoxicity: a new contributory factor for doxorubicin-mediated thrombocytopenia
Doxorubicin-induced platelet cytotoxicity: a new contributory factor for doxorubicin-mediated thrombocytopenia
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DOI：
10.1111/j.1538-7836.2009.03477.x
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发表时间：
2009-07-01
影响因子：
10.4
通讯作者：
Chung, J. -H.
中科院分区：
文献类型：
--
作者：
Kim, E. -J.;Lim, K. -M.;Chung, J. -H.
背景资料：多柔比星（DOX）是一种广泛应用于实体瘤和恶性血液病的抗癌药物，但其积极使用受到严重不良反应的阻碍，包括血小板减少症。虽然DOX的骨髓毒性被认为是血小板计数减少的唯一机制，但DOX对血小板的直接影响从未被研究过。目的：本文研究了阿霉素诱导的血小板细胞毒性及其机制，旨在阐明血小板细胞毒性在阿霉素诱导的血小板减少症中的作用。结果：在新鲜分离的人血小板中，DOX以时间依赖性和浓度依赖性方式诱导血小板细胞毒性。活性氧（ROS）的产生，降低谷胱甘肽水平和随后的蛋白质巯基耗尽被证明是基础的阿霉素诱导的血小板细胞毒性。明显地，DOX处理的血小板显示凋亡特征，如半胱天冬酶-3活化、线粒体跨膜电位降低和磷脂酰丝氨酸暴露。半胱天冬酶原-3的谷胱甘肽化减少被证明是蛋白巯基耗尽和半胱天冬酶-3活化之间的联系。值得注意的是，DOX介导的血小板细胞毒性被剪切应力显著增强，剪切应力是癌症患者中常见的并发因素。这些体外结果通过体内动物模型进一步证实，其中给予DOX诱导血小板计数降低、ROS产生、半胱天冬酶-3活化、蛋白硫醇耗竭和血小板完整性受损。结论：我们证明DOX可以通过ROS产生、谷胱甘肽水平降低和蛋白巯基耗竭直接诱导血小板细胞毒性。我们认为，这项研究提供了重要的证据，阿霉素诱导的血小板细胞毒性的作用，在阿霉素治疗的患者血小板减少症的发展。
Background: Doxorubicin (DOX) is a widely used anticancer drug for solid tumors and hematologic malignancy, but its active use is hampered by serious adverse effects, including thrombocytopenia. Although bone marrow toxicity of DOX has been suggested to be the sole mechanism underlying the reduced platelet counts, the direct effects of DOX on platelets have never been examined. Objective: Here, we investigated the DOX-induced platelet cytotoxicity and its underlying mechanism in an effort to elucidate the contribution of platelet cytotoxicity to DOX-induced thrombocytopenia. Results: In freshly isolated human platelets, DOX induced platelet cytotoxicity in a time-dependent and concentration-dependent manner. Reactive oxygen species (ROS) generation, decreased glutathione levels and subsequent protein thiol depletion were shown to underlie the DOX-induced platelet cytotoxicity. Conspicuously, DOX-treated platelets displayed apoptotic features such as caspase-3 activation, reduced mitochondrial transmembrane potential, and phosphatidylserine exposure. Decreased glutathiolation of procaspase-3 was shown to be a link between protein thiol depletion and caspase-3 activation. It is of note that DOX-mediated platelet cytotoxicity was significantly enhanced by shear stress, a common complicating factor in cancer patients. These in vitro results were further confirmed by an in vivo animal model, where administration of DOX induced a platelet count decrease, ROS generation, caspase-3 activation, protein thiol depletion, and damaged platelet integrity. Conclusion: We demonstrated that DOX can directly induce platelet cytotoxicity through ROS generation, decreased glutathione levels, and protein thiol depletion. We believe that this study provides important evidence for the role of DOX-induced platelet cytotoxicity in the development of thrombocytopenia in DOX-treated patients.