Georg T Wondrak
Assistant Professor
Department:
Pharmacology and Toxicology
(520) 626-9017
Fax:
(520) 626-3797
E-mail:
Location:
Arizona Cancer Center 3979, 3977C
Bio / Research:
Redox Drug Discovery Targeting Human Skin Cancer
My drug discovery research program examines the pathological role of reactive oxygen (‘ROS’) and reactive carbonyl species (‘RCS’) in skin carcinogenesis and aims at targeting these reactive intermediates using novel reactivity-based therapeutics for photo-chemoprevention and cancer chemotherapy. In contrast to structure-based approaches that target macromolecules by selective ligands, reactivity-based drug discovery uses chemical reactants such as small molecule catalytic antioxidants, redox cyclers, and carbonyl scavengers as therapeutics that target reactive chemical species involved in human pathology. Three synergistic research projects are currently pursued in the Wondrak laboratory:
I. Targeting Metabolic Control of Melanoma Cell Survival: Altered survival signaling is a hallmark of malignant melanoma cells resulting in resistance to drug-induced apoptosis. Previous studies suggest that cancer cell survival depends on the modulation of cell death pathways by methylglyoxal (‘MG’), a reactive by-product of glycolysis, that acts by posttranslational modification and functional alteration of target proteins involved in cellular survival. We are currently testing the hypothesis that the glycolytic control of melanoma cell survival is mediated by MG-adducted heat shock protein 27 (‘MG-Hsp27’), a novel therapeutic target amenable to small molecule modulation by specific MG-antagonists [‘carbonyl scavengers’].
II. Targeting the Redox Achilles Heel of Melanoma. Recent research suggests that redox dysregulation originating from metabolic alterations and dependence on mitogenic and survival signaling through ROS represents a specific vulnerability of malignant cells that can be selectively targeted by redox chemotherapeutics. We are therefore aiming at drug discovery and target identification of experimental redox chemotherapeutics with anti-melanoma activity in vitro and in vivo [‘prooxidant redox modulators’].
III. SPA-Inducers for Photo-chemoprevention of Skin Cancer. We are also aiming at the design of small molecule biological response inducers as pharmocological activators of the innate skin photo-adaptive response (‘SPA’). These reactivity-based SPA-inducers represent a completely novel class of skin photoprotective agents currently under development in our laboratory [‘Nrf2 activators’ and ‘heat shock response inducers’].
Publications:Selected Publications
‘Redox-directed Cancer Therapeutics: Molecular Mechanisms and Opportunities.’ Wondrak GT. Antioxid Redox Signal. 2009 Jun 4. [Epub ahead of print]
‘Antimelanoma activity of the redox dye DCPIP (2,6-dichlorophenolindophenol) is antagonized by NQO1.’ Cabello CM, Bair WB 3rd, Bause AS, Wondrak GT. Biochem Pharmacol. 2009 Aug 15;78(4):344-54.
‘The experimental chemotherapeutic N6-furfuryladenosine (kinetin-riboside) induces rapid ATP depletion, genotoxic stress, and CDKN1A(p21) upregulation in human cancer cell lines.’ Cabello CM, Bair WB 3rd, Ley S, Lamore SD, Azimian S, Wondrak GT. Biochem Pharmacol. 2009 Apr 1;77(7):1125-38.
‘The cinnamon-derived Michael acceptor cinnamic aldehyde impairs melanoma cell proliferation, invasiveness, and tumor growth.’ Cabello CM, Bair WB 3rd, Lamore SD, Ley S, Bause AS, Azimian S, Wondrak GT. Free Radic Biol Med. 2009 Jan 15;46(2):220-31.
‘Cinnamoyl-based Nrf2-activators targeting human skin cell photo-oxidative stress.’ Wondrak GT, Cabello CM, Villeneuve NF, Zhang S, Ley S, Li Y, Sun Z, Zhang DD. Free Radic Biol Med. 2008 Aug 15;45(4):385-95. Epub 2008 Apr 26.
‘Reactivity-based drug discovery using vitamin B(6)-derived pharmacophores.’ Wondrak GT. Mini Rev Med Chem. 2008 May;8(5):519-28. Review.
‘Experimental therapeutics: targeting the redox Achilles heel of cancer.’ Cabello CM, Bair WB 3rd, Wondrak GT. Curr Opin Investig Drugs. 2007 Dec;8(12):1022-37. Review.
‘NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis.’ Wondrak GT. Free Radic Biol Med. 2007 Jul 15;43(2):178-90.
‘Let the sun shine in: mechanisms and potential for therapeutics in skin photodamage.’ Wondrak GT. Curr Opin Investig Drugs. 2007 May;8(5):390-400. Review.
‘Endogenous UVA-photosensitizers: mediators of skin photodamage and novel targets for skin photoprotection.’ Wondrak GT, Jacobson MK, Jacobson EL. Photochem Photobiol Sci. 2006 Feb;5(2):215-37. Review.
‘Antimelanoma activity of apoptogenic carbonyl scavengers.’ Wondrak GT, Jacobson MK, Jacobson EL. J Pharmacol Exp Ther. 2006 Feb;316(2):805-14.