Department of Pharmacology & Chemical Biology at the University of Pittsburgh
Jack C. Yalowich, PhD
Adjunct Professor
The Ohio State University, School of Pharmacy. Chair, Division of Pharmacology, 532 Parks Hall. 500 West 12th Avenue
Columbus, OH 43210

Email:
yalowich.1@osu.edu
Phone: 614-688-5980

Fax: 614-292-9083


Education
BA (Chemistry/Biology), Lehigh University, 1974.
PhD (Biochemical Pharmacology), S.U.N.Y. at Buffalo, 1980.
Postdoctoral Fellow, Medical College of Virginia, 1980-1983.


Research Areas
Protein Kinases & Phosphatases
Drug Discovery
Cancer Pharmacology
Photo of Jack C. Yalowich, PhD

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.





Important Publications
Hasinoff BB, X Wu, D Patel, R Kanagabasai, S Karmahapatra and  JC Yalowich.  Mechanisms of action and reduced cardiotoxicity of pixantrone; a topoisomerase II targeting agent with specificity for the topoisomerase IIα isoform. J. Pharm Expt. Ther. 356:397-409, 2016.
Nagre NN, S Wang, T Kellet, R Kanagasabai, J Deng, M Nishi, K Shilo, RA Oeckler, JC Yalowich, H Takashima, JW Christman, RD Hubmayr and X Zhao. TRIM72 modulates caveolar endocytosis in repair of lung cells. Am. J. Physiol. Lung Cell Mol. Physiol. 310:L452-464, 2016.
Hasinoff BB, X Wu, AA Yadav, D Patel, H Zhang, DW Wang, ZS Chen and JC Yalowich. Cellular mechanisms of the cytotoxicity of the anticancer drug elesclomol and its complex with Cu(II).  Biochem. Pharmacol. 93:266-276, 2015.
Elton TS and JC Yalowich. Experimental procedures to identify and validate specific mRNA targets of miRNAs. EXCLI J. 14:758-790, 2015.
Yadav AA, X Wu, D Patel, JC Yalowich and Hasinoff, B.B.. Structure-based design, synthesis and biological testing of etoposide analog epipodophyllotoxin-N-mustard hybrid compounds designed to covalently bind to topoisomerase II and DNA. Biorg. Med. Chem. 22:5935-5949, 2014.
Ren Y, DD Lantvit, Y Deng, R Kanagasabai, JC Gallucci, TN Ninh, HB Chai, DD Soejarto, JR Fuchs, JC Yalowich, J Yu, SM Swanson and AD Kinghorn. Potent cytotoxic arylnaphthalene lignan lactones from Phyllanthus poilanei. J. Nat. Prod. 77:1494-1504, 2014.
Yalowich JC, X Wu, R Zhang, R Kanagasabai, M Hornbaker and BB Hasinoff. The anticancer thiosemicarbazones Dp44mT and triapine lack inhibitory effects as catalytic inhibitors or poisons of DNA topoisomerase IIα.Biochemical pharmacology. 84:52-58, 2012.
Hasinoff BB, X Wu, JL Nitiss, R Kanagasabai and JC Yalowich.  The anticancer multi-kinase inhibitor dovitinib also targets topoisomerase I and topoisomerase II.  Biochem Pharmacol 84:1617-1626, 2012.
Zhang R, X Wu, JC Yalowich and BB Hasinoff. Design, synthesis, and biological evaluation of a novel series of bisintercalating DNA-binding piperazine-linded bisanthrapyrazole compounds as anticancer agents. Bioorganic & Med Chem. 19:7023-7032, 2011.
Wu X, JC Yalowich and BB Hasinoff. Cadmium is a catalytic inhibitor of DNA topoisomerase II. J. Inorganic Biochem. 105:833-838, 2011.
Vlasova II, WH Feng, JP Goff, A Giorgianni, D Do, SM Gollin, DW Lewis, VE Kagan and JC Yalowich. Myeloperoxidase-dependent oxidation of etoposide in human myeloid progenitor CD34+ cells. Mol Pharmacol. 79:479-487, 2011.




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