Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.
Mol Pharmacol. 2011 Mar;79(3):479-87. doi: 10.1124/mol.110.068718. Epub 2010 Nov 19.
Etoposide is a widely used anticancer drug successfully used for the treatment of many types of cancer in children and adults. Its use, however, is associated with an increased risk of development of secondary acute myelogenous leukemia involving the mixed-lineage leukemia (MLL) gene (11q23) translocations. Previous studies demonstrated that the phenoxyl radical of etoposide can be produced by action of myeloperoxidase (MPO), an enzyme found in developing myeloid progenitor cells, the likely origin for myeloid leukemias. We hypothesized, therefore, that one-electron oxidation of etoposide by MPO to its phenoxyl radical is important for converting this anticancer drug to genotoxic and carcinogenic species in human CD34(+) myeloid progenitor cells. In the present study, using electron paramagnetic resonance spectroscopy, we provide conclusive evidence for MPO-dependent formation of etoposide phenoxyl radicals in growth factor-mobilized CD34(+) cells isolated from human umbilical cord blood and demonstrate that MPO-induced oxidation of etoposide is amplified in the presence of phenol. Formation of etoposide radicals resulted in the oxidation of endogenous thiols, thus providing evidence for etoposide-mediated MPO-catalyzed redox cycling that may play a role in enhanced etoposide genotoxicity. In separate studies, etoposide-induced DNA damage and MLL gene rearrangements were demonstrated to be dependent in part on MPO activity in CD34(+) cells. Together, our results are consistent with the idea that MPO-dependent oxidation of etoposide in human hematopoietic CD34(+) cells makes these cells especially prone to the induction of etoposide-related acute myeloid leukemia.
依托泊苷是一种广泛应用的抗癌药物，成功地用于治疗儿童和成人的多种癌症。然而，其使用与涉及混合谱系白血病（MLL）基因（11q23）易位的继发性急性髓系白血病的发展风险增加有关。先前的研究表明，依托泊苷的苯氧自由基可以通过髓过氧化物酶（MPO）的作用产生，MPO 是一种存在于发育中的髓样祖细胞中的酶，可能是髓样白血病的起源。因此，我们假设 MPO 对依托泊苷的单电子氧化作用将其转化为人类 CD34+髓样祖细胞中的遗传毒性和致癌物质对于将这种抗癌药物转化为遗传毒性和致癌物质非常重要。在本研究中，我们使用电子顺磁共振波谱法，为 MPO 依赖性地在从人脐带血中分离的生长因子动员的 CD34+细胞中形成依托泊苷苯氧自由基提供了确凿的证据，并证明在存在苯酚的情况下，MPO 诱导的依托泊苷氧化被放大。依托泊苷自由基的形成导致内源性巯基的氧化，从而为依托泊苷介导的 MPO 催化的氧化还原循环提供了证据，该循环可能在增强依托泊苷遗传毒性中起作用。在单独的研究中，证明依托泊苷诱导的 DNA 损伤和 MLL 基因重排部分依赖于 CD34+细胞中的 MPO 活性。总之，我们的结果与 MPO 依赖性地在人类造血 CD34+细胞中氧化依托泊苷的观点一致，这使得这些细胞特别容易受到依托泊苷相关的急性髓系白血病的诱导。
