Mechanisms of Cancer Chemoprevention by Novel agents that release Gaseous mediators
My research examines the signaling pathways that play roles in carcinogenesis and progression of cancers of colorectal, breast, pancreas including T-cell leukemia, with the goal of regulating these pathways by novel compounds that release gasotransmitters, such as nitric oxide and hydrogen sulfide. The novel agents are derivatives of non-steroidal anti-inflammatory drugs (NSAIDs), for example, aspirin and are examined in appropriate cell culture and animal models.
Main focus of study are mechanisms of cancer chemoprevention through modulation of the Wnt/ beta-catenin signaling pathway which is a dysregulated early event in colorectal cancer, as well as the interplay of transcription factor NF-kappaB, the enzyme cyclooxygenase-2, nitric oxide synthase enzyme, MAP kinases and apoptotic pathway proteins on cell growth, apoptosis and inflammation. The questions posed at the molecular level are possibility of signaling through protein nitrosylation or protein sulfhydration.
Other interests include investigating these and other novel agents for anti-cancer effects by 3-dimensional arrays that simulate the tumor environment.
Nath N, Kashfi K, Chen J, Rigas B. NO-donating aspirin inhibits beta-catenin/TCF signaling in SW480 colon cancer cells by disrupting the nuclear beta-catenin-TCF association. Proc Natl Acad Sci USA, 2003; 100:12584-9.
Nath N, Chattopadhyay M, Pospishil L, Cieciura LZ, Goswami S, Kodela R, Saavedra JE, Keefer LK, Kashfi K. JS-K, a nitric oxide-releasing prodrug, modulates beta-catenin/TCF signaling in leukemia Jurkat cells: evidence of an S-nitrosylated mechanism. Biochem Pharmacol. 2010;80:1641-9.
Nath N, Chattopadhyay M, Kodela R, Tian S, Vlismas P, Boring D, Crowell JA, Kashfi K. Modulation of stress genes expression profile by nitric oxide-releasing aspirin in Jurkat T leukemia cells. Biochem Pharmacol. 2010;79:1759-71.
Williams JL, Nath N, Chen J, Hundley TR, Gao JJ, Kashfi K, Rigas B. Growth inhibition of human colon cancer cells by NO-donating aspirin is associated with COX-2 induction and β-catenin/TCF signaling, NF-kB and NOS2 inhibition: Implications for chemoprevention. Cancer Res, 2003; 63:7613-7618
Nath, N *, Vassel R, Chattopadhyay M, Kogan, M and Kashfi, K. Nitro-aspirin inhibits MCF-7 breast cancer cell growth: Effects on COX-2 expression and Wnt/beta-catenin/TCF-4 signaling. Biochem Pharmacol. 2009, 78:1298-1304