Myeloperoxidase-Dependent Oxidation of Etoposide in Human Myeloid Progenitor CD34(+) Cells

Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.
Molecular pharmacology (Impact Factor: 4.13). 03/2011; 79(3):479-87. DOI: 10.1124/mol.110.068718
Source: PubMed


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.

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Available from: Susanne M Gollin, Feb 21, 2014
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    • "The oxidative stress caused by toxic etoposide radicals may enhance oxidative DNA damage and topoisomerase II-dependent recombination (Vlasova et al., 2011). In addition , DNA damage leads to apoptosis and the inhibition of proliferation, and is partly responsible for myelo- suppression. "
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    ABSTRACT: The protective action of quercetin against the pro-oxidant and apoptotic effect of etoposide was investigated in HL-60 cells with a high level of myeloperoxidase (MPO) activity and in cells treated with MPO inhibitor, 4-aminobenzoic acid hydrazide (ABAH). Quercetin significantly protected MPO-rich cells against the pro-oxidative (p < 0.05) and apoptotic (p < 0.05) effects of etoposide. Pre-treatment with ABAH abolished this protective influence of quercetin on apoptosis induced by etoposide but actually enhanced the action effect of quercetin against etoposide-generated reactive oxygen species (ROS) level by this cytostaic drug. Thus quercetin can protect HL-60 cells against the pro-oxidative activity of etoposides regardless of MPO activity.
    Full-text · Article · Dec 2014 · Acta biochimica Polonica
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    • "It has been reported that VP-16 metabolites increase Topo II–dependent cleavage near leukemia-associated MLL translocation breakpoints (Lovett et al., 2001). Furthermore , Vlasova et al. (2011) have shown that the VP-16 radical formed from 1-electron oxidation can redox cycle, leading to enhanced Topo II–mediated strand breaks and MLL gene translocation. Our previous studies have shown that VP-16 is readily oxidized by × NO chemistry to its phenoxyl radical, an obligatory intermediate in the formation of the VP-16-o- quinone (Sinha et al., 2013). "
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    ABSTRACT: Nitric oxide (NO) was originally identified as an innate cytotoxin. However, in tumors it can enhance resistance to chemotherapy and exacerbate cancer progression. Our previous studies have indicated that NO/NO-derived species react with etoposide (VP-16) in vitro and form products that show significantly reduced activity towards HL60 cells and lipopolysaccharide (LPS)-induced macrophages. Here, we have examined the interactions of NO with VP-16 in inducible nitric oxide synthase (iNOS)-expressing human melanoma A375 cells to further confirm the hypothesis that NO generation contributes to VP-16 resistance in cancer cells. We also examined the interactions of NO with another topoisomerase active drug, adriamycin. Inhibition of iNOS catalysis by N(6)-(1-iminoethyl)-L-lysine dihydrochloride (L-NIL) in human melanoma A375 cells reversed VP-16 resistance, leading to increased DNA damage and apoptosis. Furthermore, we found that co-culturing A375 melanoma cells with LPS-induced macrophage RAW cells also significantly reduced VP-16 cytotoxicity and DNA damage in A375 cells. In contrast, NO caused no significant modulation of cytotoxicity or adriamycin-dependent apoptosis, suggesting that NO did not interact with adriamycin. Our studies support the hypothesis that NO oxidative chemistry can detoxify VP-16 through direct nitrogen oxide radical attack and provide insights into the pharmacology and anticancer activities of VP-16 that may ultimately contribute to increased resistance, treatment failure, and induction of secondary leukemia in VP-16-treated patients.
    Full-text · Article · Sep 2013 · Journal of Pharmacology and Experimental Therapeutics
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    • "Recently, the existence of a correlation has been confirmed between etoposide phenoxyl radical formation and etoposide-induced mixed-lineage leukemia gene rearrangements, which are detected in t-AML. These studies were performed on human myeloid progenitor CD34 + cells, which are probably subjected to malignant transformations, contributing to the development of secondary AML (Vlasova et al., 2011). A serious, frequent side effect induced by etoposide is also myelosuppression , limiting the use of this drug (Hande, 1992; Kobayashi and Ratain, 1994). "
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    ABSTRACT: Oxidative DNA damage, caused by etoposide cytostatic drug in healthy myeloid precursors, is likely to contribute to the development of treatment-related acute myeloid leukemia (t-AML) in some cancer patients. A frequent side effect of etoposide is myelosuppression, which restricts the use of this drug. Antioxidants from the polyphenol group have the potential to limit this damage. The aim of this study was to determine the effect of (-)-epicatechin and curcumin on DNA damage and myelosuppression induced by etoposide in bone marrow cells of male rats. Rats were treated with the following: 1) (-)-epicatechin [20 and 40 mg/kg body weight (b.w.) by gavage] or curcumin (100 and 200 mg/kg b.w. by gavage) for 7 days; 2) etoposide (50 mg/kg b.w., intraperitoneally) for 3 days; 3) (-)-epicatechin or curcumin for 4 days, followed by coadministration of etoposide for the last 3 days of the experiment; and 4) solvents of the examined compounds (control group). Bone marrow cells were isolated, and DNA damage was analyzed by comet assay. Bone marrow smears were evaluated cytologically. Etoposide administration induced serious DNA damage and hypoplasia of bone marrow. Both curcumin and (-)-epicatechin significantly attenuated etoposide-induced oxidative DNA damage. Curcumin also significantly reduced the DNA strand break and hypoplasia caused by cytostatic drug. This polyphenol increased the percentage of granulocytic precursors and lymphocytes diminished by etoposide. Curcumin exerted greater protection than (-)-epicatechin against undesirable effects induced by the cytostatic.
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