Georg Wondrak, PhD
Redox Drug Discovery Targeting Skin Cancer and Solar Photodamage
My drug discovery research program examines the pathological role of oxidative and proteotoxic stress in skin carcinogenesis and solar photodamage. The following synergistic research projects are currently pursued in the Wondrak laboratory:
I. Stress Response Pathways in Cancer
Molecular Mechanisms and Therapeutic Opportunities It is now established that the interplay between environmental exposure and molecular stress response pathways plays a critical role in skin health and disease. Likewise, dysregulated cell stress response pathways play a critical role in tumorigenesis, and a refined mechanistic understanding of this phenomenon at the molecular level promises to open new avenues for targeted therapeutic strategies that may benefit patients in the near future. The following books focusing on the role of genotoxic, proteotoxic, oxidative, metabolic, and inflammatory stress in health and tumorigenesis have been published:
1.'Stress Response Pathways in Cancer’, 2015, Springer [ISBN 978-94-017-9420-6] http://www.springer.com/biomed/cancer/book/978-94-017-9420-6
2.‘Skin Stress Response Pathways: Environmental Factors and Molecular Opportunities’, 2016, Springer [ISBN 978-3-319-43157-4] http://www.springer.com/us/book/9783319431550
II. Molecular Mechanisms of Photo-Oxidative Stress Underlying Skin Photodamage and Carcinogenesis
My long-term research interest has identified molecular pathways that contribute to skin photooxidative stress (such as endogenous photosensitizer chromophores producing reactive oxygen species upon UVA-photoexcitation), contributing to skin photodamage and UV-photocarcinogenesis. We have recently elucidated a novel pathway of UVA-induced cutaneous proteotoxicity that operates through photo-oxidative inactivation of redox-sensitive, cysteine-dependent cathepsins (CTSB, CTSL) causing autophagic-lysosomal blockade and interference with lysosomal proteolytic clearance of photo-damaged proteins and organelles. In a 2015 research paper, we have successfully identified the most potent endogenous UVA-photosensitizer and aryl hydrocarbon receptor (AhR) agonist ever described in human skin.
III. SPA-Inducers for Photo-Chemoprevention of Skin Cancer and Solar Photodamage
For skin photoprotection and improved photo-chemoprevention we are aiming at the design of pharmacological activators of the innate skin photo-adaptive response (SPA) that antagonizes cutaneous damage from environmental UV exposure. Non-cytotoxic small molecule SPA-inducers, acting through Nrf2-activation and heat shock response upregulation, represent a novel class of topical agents targeting skin photo-oxidative stress.
IV. Targeting the Redox Achilles Heel of Melanoma
Our recent research suggests that redox dysregulation originating from metabolic alterations and dependence on mitogenic and survival signaling through reactive oxygen species represents a specific vulnerability of melanoma cells that can be selectively targeted by apoptogenic redox chemotherapeutics. We are therefore aiming at drug discovery and target identification of small molecule prooxidant modulators including genotype-directed quinones and synthetically-lethal endoperoxides displaying anti-melanoma activity in vitro and in vivo.
V. Novel Molecular Strategies Targeting Glycolytic Control of Melanoma Cell Survival
Our previous studies have focused on cellular carbonyl stress modulated by glyoxalase I [lactoylglutathione lyase (EC 220.127.116.11) encoded by GLO1], a ubiquitous cellular defense enzyme involved in the detoxification of methylglyoxal (MG), a cytotoxic byproduct of glycolysis. We were the first group to demonstrate massive overexpression of GLO1 in malignant melanoma substantiating the hypothesis that overexpression of GLO1 in metastatic melanoma tissue may represent an indispensable survival factor enabling high glycolytic flux (associated with elevated MG production) under hypoxic conditions. We are currently engaged in testing feasibility of undermining glycolytic performance and hypoxic adaptations of malignant melanoma cells by targeting GLO1 using novel structure-based small molecular inhibitors.
VI. Molecular Strategies for Improved Cancer Chemoprevention: Focus on Cinnamon
For cancer chemoprevention and antioxidant protection from environmental insult, we are aiming at the discovery and design of redox-directed activators of biological stress response pathways, a project pursued in close collaboration with Dr. Donna Zhang, College of Pharmacy. Screening synthetic and food factor-derived compound libraries, we engage in the identification of small molecule cytoprotectants including inducers of the Nrf2/Keap1-orchestrated antioxidant defense and activators of the HSF1 (heat shock factor 1)-orchestrated heat shock response in epithelial cells. We are particularly interested in the chemopreventive development of cytoprotective biofactors derived from cinnamon (cinnamaldehyde) and edible plants of the American Southwest (e.g. betalain-pigments from prickly pear and saguaro fruits).
The tryptophan-derived endogenous arylhydrocarbon receptor ligand 6-formylindolo[3,2-b]carbazole (FICZ) is a nanomolar UVA-photosensitizer in epidermal keratinocytes. Park SL, Justiniano R, Williams JD, Cabello CM, Qiao S, Wondrak GT. J Invest Dermatol. 2015 Jun;135(6):1649-58.
Nrf2-dependent suppression of azoxymethane/dextran sulfate sodium-induced colon carcinogenesis by the cinnamon-derived dietary factor cinnamaldehyde. Long M, Tao S, Rojo de la Vega M, Jiang T, Wen Q, Park SL, Zhang DD, Wondrak GT. 2015 Cancer Prev Res (Phila) 8(5):444-54.
The quinone methide aurin is a heat shock response inducer that causes proteotoxic stress and Noxa-dependent apoptosis in malignant melanoma cells. Davis AL, Qiao S, Lesson JL, Rojo de la Vega M, Park SL, Seanez CM, Gokhale V, Cabello CM, Wondrak GT. 2015 J Biol Chem. 290(2):1623-38.
Malondialdehyde-derived epitopes in human skin result from acute exposure to solar UV and occur in nonmelanoma skin cancer tissue.
Williams JD, Bermudez Y, Park SL, Stratton SP, Uchida K, Hurst CA, Wondrak GT. J Photochem Photobiol B. 2014 Mar 5;132:56-65.
The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death. Qiao S, Tao S, Rojo de la Vega M, Park SL, Vonderfecht AA, Jacobs SL, Zhang DD, Wondrak GT. Autophagy. 2013 Dec;9(12):2087-102
UVA causes dual inactivation of cathepsin B and L underlying lysosomal dysfunction in human dermal fibroblasts. Lamore SD, Wondrak GT, J Photochem Photobiol B. 2013 Jun 5;123:1-12.
D-Penicillamine targets metastatic melanoma cells with induction of the unfolded protein response (UPR) and Noxa (PMAIP1)-dependent mitochondrial apoptosis. Qiao S, Cabello CM, Lamore SD, Lesson JL, Wondrak GT, Apoptosis. 2012 Oct;17(10):1079-94.
The redox antimalarial dihydroartemisinin targets human metastatic melanoma cells but not primary melanocytes with induction of NOXA-dependent apoptosis. Cabello CM, Lamore SD, Bair WB 3rd, Qiao S, Azimian S, Lesson JL, Wondrak GT, Invest New Drugs. 2012 Aug;30(4):1289-301.
Thiostrepton is an inducer of oxidative and proteotoxic stress that impairs viability of human melanoma cells but not primary melanocytes. Qiao S, Lamore SD, Cabello CM, Lesson JL, Muñoz-Rodriguez JL, Wondrak GT, Biochem Pharmacol. 2012 May 1;83(9):1229-40. doi: 10.1016/j.bcp.2012.01.027. Epub 2012 Feb 1.
Autophagic-lysosomal dysregulation downstream of cathepsin B inactivation in human skin fibroblasts exposed to UVA. Lamore SD, Wondrak GT, Photochem Photobiol Sci. 2012 Jan;11(1):163-72.
Phenotypic identification of the redox dye methylene blue as an antagonist of heat shock response gene expression in metastatic melanoma cells. Davis AL, Cabello CM, Qiao S, Azimian S, Wondrak GT. Int J Mol Sci. 2013 Feb 19;14(2):4185-202.
The redox antimalarial dihydroartemisinin targets human metastatic melanoma cells but not primary melanocytes with induction of NOXA-dependent apoptosis. Cabello CM, Lamore SD, Bair WB 3rd, Qiao S, Azimian S, Lesson JL, Wondrak GT. Invest New Drugs. 2011 May 6. [Epub ahead of print]
Lamore SD, Wondrak GT.Zinc pyrithione impairs zinc homeostasis and upregulates stress response gene expression in reconstructed human epidermis. Biometals. 2011 Mar 22. [Epub ahead of print]
Cabello CM, Lamore SD, Bair WB 3rd, Davis AL, Azimian SM, Wondrak GT.DCPIP (2,6-dichlorophenolindophenol) as a genotype-directed redox chemotherapeutic targeting NQO1*2 breast carcinoma. Free Radic Res. 2011 Mar;45(3):276-92. Epub 2010 Nov 1.
Proteomic identification of cathepsin B and nucleophosmin as novel UVA-targets in human skin fibroblasts. Lamore SD, Qiao S, Horn D, Wondrak GT. Photochem Photobiol. 2010 Nov-Dec;86(6):1307-17.
The malondialdehyde-derived fluorophore DHP-lysine is a potent sensitizer of UVA-induced photooxidative stress in human skin cells. Lamore SD, Azimian S, Horn D, Anglin BL, Uchida K, Cabello CM, Wondrak GT. J Photochem Photobiol B. 2010 Dec 2;101(3):251-64.
The cinnamon-derived dietary factor cinnamic aldehyde activates the Nrf2-dependent antioxidant response in human epithelial colon cells. Wondrak GT, Villeneuve NF, Lamore SD, Bause AS, Jiang T, Zhang DD. Molecules. 2010 May 7;15(5):3338-55.
Resveratrol prevents epigenetic silencing of BRCA-1 by the aromatic hydrocarbon receptor in human breast cancer cells.Papoutsis AJ, Lamore SD, Wondrak GT, Selmin OI, Romagnolo DF. J Nutr. 2010 Sep;140(9):1607-14.
HMGB1-directed drug discovery targeting cutaneous inflammatory dysregulation. Lamore SD, Cabello CM, Wondrak GT. Curr Drug Metab. 2010 Mar;11(3):250-65. Review.
GLO1 overexpression in human malignant melanoma. Bair WB 3rd, Cabello CM, Uchida K, Bause AS, Wondrak GT. Melanoma Res. 2010 Apr;20(2):85-96.
The topical antimicrobial zinc pyrithione is a heat shock response inducer that causes DNA damage and PARP-dependent energy crisis in human skin cells. Lamore SD, Cabello CM, Wondrak GT. Cell Stress Chaperones. 2010 May;15(3):309-22.
Redox-directed cancer therapeutics: molecular mechanisms and opportunities. Wondrak GT. Antioxid Redox Signal. 2009 Dec;11(12):3013-69. Review.
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.
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.