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Research Description:
Recent studies are focused on understanding the mechanisms by which the clinically effective anticancer agent etoposide (VP-16), a phenolic compound, and the environmental carcinogen, benzene, cause acute myelogenous leukemia (AML). The central testable hypothesis is that redox cycling of VP-16 and phenolic benzene metabolites initiated by myeloperoxidase (MPO) in bone marrow precursors amplifies the genotoxicity and carcinogenicity of these compounds via enhanced topo II inhibition. Nutritional antioxidants such as vitamin C and vitamin E homologs are under investigation as a mechanism-based chemo-prevention strategy to eliminate VP-16- and benzene-induced AML by reducing production of peroxidase-dependent free radical and electrophilic metabolites. The long-term goal of these studies is to increase the clinical efficacy of VP-16 in the treatment of cancer, and to prevent benzene leukemogenesis. I. Etoposide (VP-16)-related secondary myeloid leukemias (t-AML) are most frequently associated with MLL gene translocations at 11q23. Our central hypothesis is that redox cycling of VP-16 initiated by myeloperoxidase (MPO) found prominently in myeloid precursors amplifies the genotoxicity and carcinogenicity of this otherwise clinically effective DNA topoisomerase II (topo II)-targeted anticancer agent. We propose that MPO converts VP-16 to free radical species and oxidized metabolites that induce oxidative DNA damage and initiate recombinogenic events in myeloid precursor stem cells leading to the chromosomal translocations responsible for t-AML. Specifically, it is proposed: 1) that oxidative DNA damage and abasic DNA sites formed as a consequence of peroxidative activation of VP-16 result in loci that increase topo II poisoning; and/or: 2) that electrophilic VP-16-ortho-quinone formed in MPO-rich progenitors will poison topo II by adduction to sulfhydryl groups on the enzyme. We further posit that nutritional antioxidants such as vitamin C and vitamin E homologs will prevent VP-16-induced AML by reducing or preventing production of peroxidase-dependent free radical and electrophilic metabolites. We propose to determine the mechanism(s) by which peroxidative activation of VP-16 to phenoxyl radical and ortho-quinone metabolites enhances its DNA damaging and recombinogenic activities in genomic regions of the MLL gene known to contain breakpoints associated with t-AML. II. Benzene-induced acute myeloid leukemia (AML) is a result of exposure to this genotoxicant. Benzene leukemogenesis has been linked to P450-mediated metabolism of benzene to phenolic compounds. In myeloid progenitors, myeloperoxidase (MPO) converts these phenols to redox-reactive and arylating benzene metabolites such as 1,4-hydroquinone and 1,4-benzoquinone. These benzene metabolites are recently demonstrated DNA topoisomerase II (topo II) poisons like the anticancer agent etoposide (VP-16). Etoposide is a phenolic compound known to cause therapy-related AMLs associated with MLL gene translocations. Benzene-induced AML can also display MLL gene translocations. This knowledge serves as the foundation for our central hypothesis that MPO-catalyzed redox cycling of phenolic benzene metabolites in myeloid progenitors yields carcinogenic species linked to poisoning of topo II. Specifically, it is proposed: 1) that oxidative damage and abasic DNA sites formed as a consequence of peroxidative activation of benzene phenols result in loci known to poison topo II; and/or: 2) that benzoquinones formed in MPO-rich progenitors poison topo II by electrophilic adduction to critical sulfhydryl groups. We further posit that nutritional antioxidants such as vitamin C and vitamin E homologs will prevent benzene-induced AML by preventing production or scavenging of MPO-derived free radical and electrophilic metabolites.
Education:
B.A. (Chemistry/Biology), Lehigh University, 1974.
Ph.D. (Biochemical Pharmacology), S.U.N.Y. at Buffalo, 1980.
Postdoctoral Fellow, Medical College of Virginia, 1980-1983.
Important Publications:
- Fan, Y., Schreiber, E.M., Giorgianni, A., Yalowich, J.C., and Day, B.W. Myeloperoxidase-catalyzed metabolism of etoposide to quinone and glutathione adduct forms in HL60 cells. Chemical Research in Toxicology; 19(7): 937-943, 2006.
- Hasinoff, B.B., Wu, X., Begleiter, A., Guziec, L.J., Guziec Jr., F., Giorgianni, A., Yang, S., Jiang, Y., and Yalowich, J.C. Structure-activity study of the interaction of bioreductive benzoquinone alkylating agents with DNA topoisomerase II. Cancer Chemother. Pharm., 57(2):221-33, 2006.
- Hasinoff, B.B., Wu, X., Krokhin, O.V., Ens, W., Standing, K.G., Nitiss, J.L., Sivaram, T., Giorgianni, A., Yang, S., Jiang, Y., and Yalowich, J.C. Biochemical and Proteomics Approaches to Characterize Topoisomerase II Cysteines and DNA as Targets Responsible for Cisplatin-induced Inhibition of Topoisomerase II. Mol. Pharmacol., 67(3): 937-947, 2005.
- Kamath, R., Jiang, Z., Sun, G., Yalowich, J.C., and Baskaran, R. c-Abl kinase regulates curcumin-induced cell death through activation of JNK. Mol. Pharmacol., 71(1): 61-72, 2007.
- Tyurina, Y.Y., Kini, V.,Tyurin, V.A., Vlasova, I.I., Jiang, J., Kapralov, A.A., Belikova, N.A., Yalowich, J.C., Kurnikov, I.V., and Kagan, V.E. Mechanisms of cardiolipin oxidation by cytochrome c: relevance to pro- and anti-apoptotic functions of etoposide. Molecular Pharmacology, 70(2):706-17, 2006.
- Tyurina, Y.Y., Serinkan, F.B.,Tyurin V.A., Kini, V., Yalowich, J.C.,Schroit, A.J., Fadeel, B., and Kagan, V.E. Etoposide inhibits phosphatidylserine externalization by blocking its oxidation during apoptosis in HL-60 cells. Antioxidant dissociation of phosphatidylserine signaling from the final common pathway for apoptosis. J. Biol. Chem., 279: 6056-64, 2004.
- Zheng, K-C., Yalowich, J.C., Kagan, V.E., Keohavong, P. Mutagenic activity of succinyl acetone at the HPRT locus of HL-60 cells. Cell Biol Toxicol., 22(5):361-70, 2006.
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