Department of Pharmacology & Chemical Biology at the University of Pittsburgh
Kensler Lab E1316 Thomas E. Starzl Biomedical Science Tower
Pittsburgh, PA 15260

Research interests in my laboratory focus on the biochemical and molecular mechanisms involved in the induction of cancer by chemicals to serve as a basis for the prevention, interruption or reversal of these processes in man. One of the major mechanisms of chemical protection against carcinogenesis, mutagenesis and other forms of toxicity mediated by carcinogens is the induction of enzymes involved in their metabolism, particularly enzymes such as glutathione S-transferases, UDP-glucuronosyl transferases and NAD(P)H:quinone reductase that facilitate the detoxication and elimination of carcinogens. Furthermore, animal studies indicate that induction of these cytoprotective enzymes is a sufficient condition for obtaining chemoprevention and can be achieved in many target tissues by administering any of a diverse array of naturally-occurring and synthetic chemical agents. Our work utilizes animal and cell culture models to elucidate mechanisms of inhibition of aflatoxin hepatocarcinogenesis by dithiolethiones such as oltipraz, isothiocyanates such as sulforaphane and triterpenoids such as CDDO-Im. While induction of glutathione S-transferases clearly play an important role in chemoprevention of aflatoxin hepatocarcinogenesis, ongoing studies are seeking to identify additional genes induced by these agents. The Keap1-Nrf2 signaling pathway is activated by these classes of chemopreventive agents and leads to increased expression of genes that attenuate oxidative stress and inflammation among other actions. Their contributions to protection against carcinogenesis are under investigation. A practical goal of our research has been to develop the tools to test the hypothesis that enzyme induction is a useful strategy for chemoprevention in humans. Hepatocellular carcinoma is the leading cause of cancer death in parts of Asia and Africa and may relate to hepatitis B virus infection and aflatoxin ingestion. Longitudinal surveys and prospective case-control studies in Qidong, P.R. China demonstrate consistent exposure of individuals in this region to aflatoxins and indicate a prime role for aflatoxin in the etiology of liver cancer, respectively. As a consequence, we have conducted clinical chemoprevention trials of oltipraz and other agents in Qidong. The initial randomized, placebo-controlled intervention of oltipraz demonstrated an increased excretion of aflatoxin-mercapturic acid, a derivative of the aflatoxin-glutathione conjugate, in the urine of participants receiving oltipraz. This study highlights the general feasibility of inducing Nrf2-regulated enzymes in humans. Follow-up trials are evaluating more effective agents and are assessing whether protective alterations in aflatoxin metabolism can be sustained for extended periods of time and whether diminished incidence of liver cancer can be achieved in this high-risk population.

Selected Publications:

Kensler, T.W. and Wakabayashi, N. (2010) Nrf2: friend or foe for chemoprevention? Carcinogenesis 31:90-99.

Yates, M.S., Tran, Q.T., Dolan, P.D., Osburn, W.O., Shin, S., McCulloch, C.C., Silkworth, J.B., Taguchi, K., Yamamoto, M., Williams, C.R., Liby, K.T., Sporn, M.B., Sutter, T.R., and Kensler, T.W. (2009) Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid treated mice. Carcinogenesis 30: 1024-1031.

Shin, S., Wakabayashi, J., Yates, M., Wakabayashi, N., Dolan, P.M., Aja, S.M., Liby, K.T., Sporn, M.B., and Kensler, T.W. (2009) Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-Imidazolide. Europ. J. Pharmacology 620: 138-144.

Osburn, W.O., Yates, M.S., Dolan, P.M., Chen, S., Liby, K.T., Sporn, M.B., Taguchi, K., Yamamoto, M. and Kensler, T.W. (2008) Genetic or pharmacologic amplification of Nrf2 signaling inhibits acute inflammatory liver injury in mice. Toxicological Sciences 104: 218-227.

Shin, S., Wakabayashi, N., Misra, V., Biswal, S., Lee, G.H., Agoston, E.S., Yamamoto, M., and Kensler, T.W. (2007) NRF2 modulates AHR signaling: influence on adipogenesis. Molec. Cell. Biol. 27: 7188-7197.

Kensler, T.W., Wakabayashi, N., and Biswal, S. (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Ann. Rev. Pharmacol. Toxicol. 47: 89-116.

Yates, M.S., Kwak, M-K., Egner, P.A., Groopman, J.D., Bodreddigari, S., Sutter, T.R., Baumgartner, K.J., Roebuck, B.D., Yore, M.M., Honda, T., Gribble, G.W., Sporn, M.B. and Kensler, T.W. (2006) Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole. Cancer Res. 66: 2488-2494.

Kensler, T.W., Chen, J-G., Egner, P.A., Fahey, J.W., Jacobson, L.P., Stephenson, K.K., Ye, L., Coady, J.L., Wang, J-B., Wu, Y., Sun, Y., Zhang, Q-N., Zhang, B-C., Zhu, Y-R., Qian, G-S., Carmella, S.G., Hecht, S.S., Benning, L., Gange, S.J., Groopman, J.D. and Talalay, P. (2005) Effects of glucosinolate-rich broccoli sprouts on urinary levels of aflatoxin-DNA adducts and phenanthene tetraols in a randomized clinical trial in He Zuo Township, Qidong, PRC. Cancer Epidemiol. Biomarkers Prev. 14:2605-2613.  

Thomas W. Kensler, PhD

Nobunao Wakabayashi, PhD

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