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Thomas W. Kensler

Thomas W. Kensler

Department Affiliation: Primary: Environmental Health Sciences
Joint: Pharmacology and Molecular Sciences; Biochemistry and Molecular Biology; Oncology
Degree: Ph.D., MIT
Rank: Professor
Telephone Number: 410-955-1292
Fax Number: 410-955-0116
E-mail address:  tkensler@jhsph.edu
School of Public Health Address: Room E-7030, School of Public Health, 615 N. Wolfe St., Baltimore, MD 21205
                 

Mechanisms of cancer chemoprevention

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. 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 [4-methyl-5-(2-pyrazinyl)-1,2-dithole-3-thione], isothiocyanates such as sulforaphane and triterpenoids such as CDDO-Im. The Keap1-Nrf2 signaling pathway mediates some of the protective actions of these agents. Current studies using transgenic and knockout mice probe the identification and characterization of Nrf2-regulated genes in chemoprevention. Evaluation of the interactions of the Nrf2 pathway with other signaling networks and their impact on cell fate is also under investigation.

A practical goal of our research has been to develop the tools to test the hypothesis that induction of Nrf2-regulated genes 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 are conducting clinical chemoprevention trials of sulforaphane and other agents in Qidong. Our 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 cytoprotective enzymes in humans. Follow-up trials 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

Representative Publications:

  • 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-richbroccoli sprouts on urinary levels of aflatoxin-DNA adducts and phenanthenetetraols in a randomized clinical trial in He Zuo Township, Qidong, PRC. Cancer Epidemiol. Biomarkers Prev.14:2605-2613. PubMed Reference.
  • Yu, Z., Egner,P.A., Wakabayashi, J., Wakabayashi, N., Yamamoto, M. and Kensler, T.W. (2006)Nrf2-mediated induction of cytoprotective enzymes by 15-deoxy-?12,14-PGJ2is attenuated by alkenal/one oxidoreductase. J. Biol. Chem. 281: 25245-26252. PubMed Reference.
  • Yates, M.S.,Tauchi, M., Katsuoka, F., Flanders, K.C., Liby, K.T., Honda, T., Gribble, G.W.,Johnson, D.A., Johnson, J.A., Burton, N.C., Guilarte, T.R., Yamamoto,M., Sporn, M.B. and Kensler, T.W. (2007) Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers ofNrf2-regulated genes. Molec. Cancer Therapeu. 6: 154-162. PubMed Reference.
  • Cornblatt, B.S.,Ye, L., Dinkova-Kostova, A.T., Erb, M., Fahey, J.W., Singh, N.K., Chen, A-s.A.,Stierer, T., Garrett-Meyer, E., Argani, P., Davidson, N.E., Talalay, P., Kensler, T.W. and Visvanathan, K.(2007) Preclinical and clinical evaluation of sulforaphane for chemopreventionin the breast. Carcinogenesis 28:1485-1490. PubMed Reference.
  • 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. PubMed Reference.
  • Kensler, T.W., Wakabayashi, N., and Biswal, S. (2007) Cell survival responses to environmentalstresses via the Keap1-Nrf2-ARE pathway. Ann. Rev. Pharmacol. Toxicol. 47: 89-116. PubMed Reference.
  • 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. PubMed Reference.
  • Roebuck, B.D., Johnson, D.N., Sutter, C.H., Egner, P.A., Scholl, P.F., Baumgartner, J.J., Ware, N.M., Bodreddigari, S., Groopman, J.D., Kensler, T.W., and Sutter, T.R. (2009) Transgenic expression of aflatoxin aldehyde reductase (AKR7A1) modulates aflatoxin B1 metabolism but not hepatic carcinogenesis in the rat. Toxicological Sciences 109: 41-49. Pub Med Reference
  • 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. Pub Med Reference
  • 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. Pub Med Reference

Other graduate programs in which Dr. Kensler participates:

Biochemistry and Molecular Biology Program
Environmental Health Sciences


Keywords
Environmental Health Sciences, Chemical carcinogenesis, chemoprevention, hepatocarcinogenesis, reactive oxygen, antioxidants, enzyme induction, aflatoxin, oltipraz, chlorophllin

 

 
 
 
 
 
 

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