Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States and accounts for more than 50,000 deaths per year. CRC is initiated by mutations of adenomatous polyposis coli (APC) and b-catenin genes, which result in abnormal activation of the Wnt signaling pathway. Inhibition Wnt signaling is essential for CRC prevention and treatment;however, prior efforts along these lines were not successful because of the side effects displayed by these inhibitors. We hypothesize that natural products and their analogs are ideal therapeutic agents if they target key pathways in CRC and possess minimal toxicity. Recently, we reported that resveratrol, which is found in the skin of red grapes, significantly inhibits Wnt signaling. Resveratrol is reported to have anti-cancer activity and not toxic at concentration (1 gram/day) effective for CRC treatment, but resveratrol has a half-life in vivo that limits its utility as a therapeutic agent. Supported by an R21 grant (RCA139359), we designed and synthesized resveratrol analogs called FlDAS agents that are more potent than resveratrol in cell based assays and possess significantly greater half-lives than reservatrol. One particular compound, FlDAS-4r, inhibits growth of human CRC xenografts in nude mice and is well tolerated in mice. Using a biotinylated, biologically active form of FIDAS-4r, we identified methionine adenosyltransferase 2A (MAT2A) as the direct target for resveratrol analogs. Our central hypothesis is that resveratrol and its analogs inhibit MAT2A and regulate the levels and metabolism of S-adenosylmethionine (SAM), thus inhibiting Wnt signaling and the proliferation of CRC cells. To further define the molecular mechanism of these anti- cancer agents and to develop these agents for CRC treatment and chemoprevention, we will pursue the following three Specific Aims: 1) To define the mechanisms regulating inhibition of MAT2A by FIDAS agents;2) To delineate the mechanisms of how FIDAS agents inhibit CRC cell growth;and 3) To characterize novel FIDAS agents using in vivo mouse models.
Colorectal cancer is the second leading cause of cancer death in the United States. Resveratrol and its novel analogs are promising agents for colorectal cancer prevention and treatment. This project will explore novel mechanisms of action of resveratrol analogs using cell and animal models of colorectal cancer, in order to develop better chemopreventive and therapeutic agents in the future.
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|Xu, Xuehe; Yu, Tianxin; Shi, Jiandang et al. (2014) Thymine DNA glycosylase is a positive regulator of Wnt signaling in colorectal cancer. J Biol Chem 289:8881-90|
|Sviripa, Vitaliy M; Zhang, Wen; Balia, Andrii G et al. (2014) 2',6'-Dihalostyrylanilines, pyridines, and pyrimidines for the inhibition of the catalytic subunit of methionine S-adenosyltransferase-2. J Med Chem 57:6083-91|