Abstract

DT-diaphorase, although generally considered to be a protective enzyme against quinone-induced toxicity, has been suggested to play a role in the bioactivation of antitumor quinones. The precise role of DT-diaphorase in bioreductive activation of quinones remains controversial. We propose to utilize DT-diaphorase purified from HT-29 human colon carcinoma cells to examine the role of this enzyme in bioactive of AZQ* and Mitomycin C. Whether AZQ, Mitomycin C and their analogs are substrates for HT-29 DT- diaphorase and whether metabolism by this enzyme results in the production of metabolites which can induce damage to cellular macromolecules (DNA, proteins, soluble thiols) will be examined. Studies in cellular systems will also be performed to identify intracellular targets of antitumor quinones. These studies will allow unequivocal confirmation of the role of DT- diaphorase in bioreductive activation of AZQ and Mitomycin C in human tumor cells. * AZQ - Diaziquone-(2,5-bis(1-aziridinyl)-3,0-bis-(carboethoxyamino)1,4- benzoquinone.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA051210-01A1
Application #
3195951
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1990-07-01
Project End
1993-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
University of Colorado at Boulder
Department
Type
Schools of Pharmacy
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80309

  Publications

Ross, David; Siegel, David (2017) Functions of NQO1 in Cellular Protection and CoQ10 Metabolism and its Potential Role as a Redox Sensitive Molecular Switch. Front Physiol 8:595
Xiong, Rui; Zhou, Wenbo; Siegel, David et al. (2015) A Novel Hsp90 Inhibitor Activates Compensatory Heat Shock Protein Responses and Autophagy and Alleviates Mutant A53T ?-Synuclein Toxicity. Mol Pharmacol 88:1045-54
Chang, Chuan-Hsin; Drechsel, Derek A; Kitson, Russell R A et al. (2014) 19-substituted benzoquinone ansamycin heat shock protein-90 inhibitors: biological activity and decreased off-target toxicity. Mol Pharmacol 85:849-57
Kitson, Russell R A; Chang, Chuan-Hsin; Xiong, Rui et al. (2013) Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90. Nat Chem 5:307-14
Siegel, David; Yan, Chao; Ross, David (2012) NAD(P)H:quinone oxidoreductase 1 (NQO1) in the sensitivity and resistance to antitumor quinones. Biochem Pharmacol 83:1033-40
Reigan, Philip; Siegel, David; Guo, Wenchang et al. (2011) A mechanistic and structural analysis of the inhibition of the 90-kDa heat shock protein by the benzoquinone and hydroquinone ansamycins. Mol Pharmacol 79:823-32
Siegel, David; Shieh, Biehuoy; Yan, Chao et al. (2011) Role for NAD(P)H:quinone oxidoreductase 1 and manganese-dependent superoxide dismutase in 17-(allylamino)-17-demethoxygeldanamycin-induced heat shock protein 90 inhibition in pancreatic cancer cells. J Pharmacol Exp Ther 336:874-80
Guo, Wenchang; Siegel, David; Ross, David (2008) Stability of the Hsp90 inhibitor 17AAG hydroquinone and prevention of metal-catalyzed oxidation. J Pharm Sci 97:5147-57
Yan, Chao; Kepa, Jadwiga K; Siegel, David et al. (2008) Dissecting the role of multiple reductases in bioactivation and cytotoxicity of the antitumor agent 2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone (RH1). Mol Pharmacol 74:1657-65
Guo, Wenchang; Reigan, Philip; Siegel, David et al. (2008) Enzymatic reduction and glutathione conjugation of benzoquinone ansamycin heat shock protein 90 inhibitors: relevance for toxicity and mechanism of action. Drug Metab Dispos 36:2050-7

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