Department Affiliation: Part-time Primary: Pharmacology and Molecular
Sciences; Part-time Secondary: Medicine
Degree: Ph.D., Washington State University
Rank: Associate Professor
Telephone Number: 410-955-3503
Fax Number: 410-502-6818
E-mail address: firstname.lastname@example.org
School of Medicine Address: 725 N. Wolfe Street, WBSB 406, Baltimore, MD 21205
Protection against cancer – mechanisms and strategies; structure-activity relation of protective agents; inflammation and cancer; skin cancer prevention
The steady increase in the number of new cancer cases diagnosed each year highlights the urgent need for the development of strategies for prevention. It is important to understand that the disease cancer is the process of carcinogenesis itself that begins many years, often decades, before any clinical symptoms become apparent. It is imperative to overcome the “obsession” in curing advanced disease and focus on the possibilities of prevention.
Protection against cancer in animal models can be accomplished by induction of phase 2 enzymes of the xenobiotic metabolism (e.g., glutathione S-transferases, epoxide hydrolase, quinone reductase 1, heme oxygenase 1) that catalyze versatile reactions collectively leading to detoxification of electrophiles and oxidants. The expression of phase 2 genes can be elevated by a wide variety of pharmacological agents that we refer to as “inducers”, some of which are present in the human diet. Inducers react with specific cysteine sulfhydryl groups of the sensor protein Keap1, thereby allowing transcription factor Nrf2 to translocate to the nucleus and activate transcription through the antioxidant response element (ARE), an enhancer upstream regulatory element that is present on phase 2 genes. The discrete events in the mechanism of action of phase 2 inducers are a major objective of our research.
Phase 2 inducers are also anti-inflammatory, and for this activity they require some of the same cellular components (e.g., Keap1 and Nrf2) that are essential for induction of phase 2 enzymes. The anti-inflammatory and phase 2 inducer properties are common to compounds of vastly different architecture, among them plant isothiocyanates, curcuminoids, as well oleanolic acid-derived triterpenoids. Identifying the link between phase 2 induction and inhibition of inflammation through structure-activity relation studies represents another objective of our research.
In addition to biochemical studies in various in vitro and cellular systems, we also employ animal models with a recent focus on models of UV light-induced skin carcinogenesis that are highly relevant to humans who have been heavily exposed to sunlight as children, have reduced their exposure as adults, but still remain at high risk for developing skin cancer. The knowledge obtained from these animal models will allow the design of clinical trials to determine the effectiveness of phase 2 inducers in preventing the development of skin cancers in high-risk populations, such as solid organ transplant recipients who are at nearly 100-fold increased risk for skin cancer development compared to the general population.
- Dinkova-Kostova, A.T., Holtzclaw, W.D., Cole, R.N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., Talalay, P. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA 99:11908-11913, 2002. Pub Med Reference
- Dinkova-Kostova, A.T., Liby, K.T., Stephenson, K.K., Holtzclaw, W.D., Gao, X., Suh, N., Williams, C., Risingsong, R., Honda, T., Gribble, G.W., Sporn, M.B., Talalay, P. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl. Acad Sci USA 102:4584-4589, 2005. Pub Med Reference
- Ahn, Y.H., Hwang, Y., Liu, H., Wang, X.J., Zhang, Y., Stephenson, K.K., Boronina, T.N., Cole, R.N., Dinkova-Kostova, A.T., Talalay, P., Cole, P.A. Electrophilic tuning of the chemoprotective natural product sulforaphane. Proc Natl Acad Sci USA 107:9590-9595, 2010. Pub Med Reference
- Wang, X.J., Hayes, J.D., Higgins, L.G., Wolf, C.R., Dinkova-Kostova, A.T. Activation of the Nrf2 signalling pathway by copper-mediated redox cycling of para- and ortho-hydroquinones. Chem Biol. 17:75-85, 2010. Pub Med Reference
- Dinkova-Kostova A.T., Talalay, P., Sharkey, J., Zhang, Y., Holtzclaw, W.D., Wang, X.J., David, E., Schiavoni, K.H., Finlayson, S., Mierke, D.F., Honda, T. An exceptionally potent inducer of cytoprotective enzymes: elucidation of the structural features that determine inducer potency and reactivity with Keap1. J Biol Chem. 285:33747-33755, 2010. Pub Med Reference
- Zhang, Y., Ahn, Y.H., Benjamin, I.J., Honda, T., Hicks, R., Calabrese, V., Cole, P.A., Dinkova-Kostova, A.T. HSF1-dependent upregulation of Hsp70 by sulfhydryl-reactive inducers of KEAP1/NRF2/ARE pathway. Chem Biol. 18:1355-1361, 2011. Pub Med Reference
- Kalra, S., Knatko, E.V., Zhang, Y., Honda, T., Yamamoto, M., Dinkova-Kostova, A.T. Highly potent activation of Nrf2 by topical tricyclic bis(cyano enone): Implications for protection against UV radiation during thiopurine therapy. Cancer Prev Res (Phila). 5: 973-981, 2012. Pub Med Reference
- Benedict, A.L., Knatko, E.V., Dinkova-Kostaova, A.T. The indirect antioxidant sulforaphane protects against thiopurine-mediated photooxidative stress. Carcinogenesis 33: 2457-66, 2012. Pub Med Reference
- Holmström, K.M., Baird, L., Zhang, Y., Hargreaves, I., Chalasani, A., Land, J.M., Stanyer, L., Yamamoto, M., Dinkova-Kostova, A.M., Abramov, A.Y. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biology Open, 2013; in press.
- Baird, L., Llères, D., Swift, S., Dinkova-Kostova, A.T. Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex. Proc Natl Acad Sci USA, 2013; in press.
Other graduate programs in which Dr. Dinkova-Kostova participates: None