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• W2084897418 abstract "Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DCThe clinical efficacy of the anticancer agent etoposide (VP-16) is compromised by its ability to cause acute myeloid leukemias (t-AML) associated with MLL gene rearrangements. We proposed previously that myeloperoxidase (MPO) found in myeloid precursors converts the phenolic drug VP-16 to its phenoxyl radical (VP-16-O[[Unable to Display Character: ∙]]), which redox cycles, leading to the generation of reactive oxygen species, oxidative DNA damage linked to DNA topoisomerase II (topo II)-mediated strand cleavage, and resultant recombination events causal for t-AML. After knockdown with an shRNA for MPO in myeloid leukemia HL-60 cells, MPO activity was reduced to 13% of shRNA controls. In these MPO knockdown cells, VP-16-O[[Unable to Display Character: ∙]] formation and VP-16-induced topo II/DNA covalent complexes were reduced compared to shRNA controls demonstrating that VP-16 activity was, in part, dependent on MPO. MPO can also oxidize VP-16 to its ortho-quinone metabolite which is subsequently inactivated by conjugation with glutathione. The cytotoxicities of VP-16, curcumin (a phenolic agent), and a curcumin analog (FLLL-10) were increased in MPO knockdown cells compared to shRNA controls. Podophyllotoxin, the non-phenolic VP-16 parental compound, was equally cytotoxic in MPO knockdown and control cells. Additionally, the cytotoxicity of hydrogen peroxide, an MPO co-substrate, was unaffected by MPO levels. Results indicate that MPO converts VP-16 to a pro-oxidant, which leads to genotoxicity, while simultaneously protecting cells from drug-induced cytotoxicity likely by glutathione conjugation to VP-16 ortho-quinone. The combined results suggest a mechanism by which MPO-containing myeloid progenitor cells can be relatively protected against VP-16-induced apoptosis/cytotoxicity while suffering increased genotoxic and recombinogenic insults responsible for leukemogenesis. Support: NIH CA090787.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3498." @default.
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• W2084897418 date "2010-04-15" @default.
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• W2084897418 title "Abstract 3498: The cytotoxicity and genotoxicity of etoposide and other phenolic and non-phenolic agents in human myeloid leukemia HL-60 cells: role of myeloperoxidase (MPO)" @default.
• W2084897418 doi "https://doi.org/10.1158/1538-7445.am10-3498" @default.
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