Department Affiliation: Part time Primary: Pharmacology and Molecular
Sciences; Part time Secondary: Medicine
Degree: Ph.D., Washington State University
Rank: Assistant Professor
Telephone Number: 410-955-3503
Fax Number: 410-502-6818
E-mail address: adkostov@jhmi.edu
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.
Representative Publications:
- Hayes JD, Dinkova-Kostova AT, McMahon M. Cross-talk between transcription factors AhR and Nrf2: lessons for cancer chemoprevention from dioxin Toxicol Sci. 2009 Oct;111(2):199-201. Pub Med Reference
- Dinkova-Kostova AT, Fahey JW, Jenkins SN, Wehage SL, Talalay P. Rapid body weight gain increases the risk of UV radiation-induced skin carcinogenesis in SKH-1 hairless mice. Nutr Res. 2008 Aug;28(8):539-43. Pub Med Reference
- Liby K, Yore MM, Roebuck BD, Baumgartner KJ, Honda T, Sundararajan C, Yoshizawa H, Gribble GW, Williams CR, Risingsong R, Royce DB, Dinkova-Kostova AT, Stephenson KK, Egner PA, Yates MS, Groopman JD, Kensler TW, Sporn MB. A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin. Cancer Res. 2008 Aug 15;68(16):6727-33. Pub Med Reference
- Dinkova-Kostova, A.T. Phytochemicals as protectors against ultraviolet radiation: Versatility of effects and mechanisms. Planta Medica 2008, Aug 11 Epub ahead of print. Pub Med Reference.
- Liu H, Dinkova-Kostova AT, Talalay P. Coordinate regulation of enzyme markers for inflammation, and for protection against oxidants and electrophiles. Proc Natl Acad Sci USA 2008, Epub 2008 Oct 6. Pub Med Reference.
- Bensasson RV, Zoete V, Dinkova-Kostova AT, Talalay P. Two-step mechanism of induction of the gene expression of a prototypic cancer-protective enzyme by diphenols. Chem Res Toxicol. 2008; 21: 805-812. Pub Med Reference.
- Talalay P, Fahey J, Healy ZR, Wehage SL, Benedict AL, Min C, Dinkova-Kostova AT. Sulforaphane mobilizes cellular defenses that protect skin against damage by UV radiation. Proc Natl Acad Sci USA 2007; 104: 17500-17505. Pub Med Reference.
- Kerns ML, DePianto D, Dinkova-Kostova AT, Talalay P, Coulombe PA. Reprogramming of keratin biosynthesis by sulforaphane restores skin integrity in Epidermolysis Bullosa Simplex. Proc Natl Acad Sci USA 2007; 104: 14460-14465. Pub Med Reference.
Dinkova-Kostova AT, Fahey JW, Wade KL, Jenkins SN, Shapiro TA, Fuchs EJ, Kerns ML, Talalay P. Induction of phase 2 response in mouse and human skin by sulforaphane-containing broccoli sprout extracts. Cancer Epidemiol Biomarkers Prev. 2007; 16: 847-851. Pub Med Reference.
- Dinkova-Kostova, A.T., Holtzclaw WD, Kensler TW. The role of Keap1 in cellular protective responses. Chem Res Toxicol. 2005; 18: 1779-1791. Pub Med Reference.
- Dinkova-Kostova AT, Holtzclaw WD, Wakabayashi N. Keap1, the sensor for electrophiles and oxidants that regulates the phase 2 response, is a zinc-metalloprotein. Biochemistry 2005; 44: 6889-6899. Pub Med Reference.
Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, Williams C, Risingsong R, Honda T, Gribble GW, Sporn MB, Talalay P. Extremely potent triterpenoid inducers of the phase 2 response: Correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci USA 2005; 102: 4584-4589. Pub Med Reference.
Other graduate programs in which Dr. Dinkova-Kostova participates:
