RT Journal Article
SR Electronic
T1 Myeloperoxidase-dependent Oxidation of Etoposide in Human Myeloid Progenitor CD34+ Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.068718
DO 10.1124/mol.110.068718
A1 Irina I. Vlasova
A1 Wei Hong Feng
A1 Julie P. Goff
A1 Angela Giorgianni
A1 Duc Do
A1 Susanne M. Gollin
A1 Dale W. Lewis
A1 Valerian E. Kagan
A1 Jack C. Yalowich
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/11/19/mol.110.068718.abstract
AB Etoposide is a widely used anticancer drug successfully utilized for 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 (t-AML) involving 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 myeloperoxidase (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 EPR 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 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 hematopoetic CD34+ cells makes these cells especially prone to induction of etoposide-related acute myeloid leukemia.