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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA172379-01A1
Application #
8576714
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Emenaker, Nancy J
Project Start
2013-08-06
Project End
2018-05-31
Budget Start
2013-08-06
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$311,250
Indirect Cost
$103,750
Name
University of Kentucky
Department
Biochemistry
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Yu, T; Chen, X; Zhang, W et al. (2016) KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer. Cell Death Differ 23:207-15
Xu, Xuehe; Watt, David S; Liu, Chunming (2016) Multifaceted roles for thymine DNA glycosylase in embryonic development and human carcinogenesis. Acta Biochim Biophys Sin (Shanghai) 48:82-9
Sviripa, Vitaliy M; Burikhanov, Ravshan; Obiero, Josiah M et al. (2016) Par-4 secretion: stoichiometry of 3-arylquinoline binding to vimentin. Org Biomol Chem 14:74-84
Frasinyuk, Mykhaylo S; Mrug, Galyna P; Bondarenko, Svitlana P et al. (2016) Antineoplastic Isoflavonoids Derived from Intermediate ortho-Quinone Methides Generated from Mannich Bases. ChemMedChem 11:600-11
Shi, Jiandang; Liu, Yajuan; Xu, Xuehe et al. (2015) Deubiquitinase USP47/UBP64E Regulates β-Catenin Ubiquitination and Degradation and Plays a Positive Role in Wnt Signaling. Mol Cell Biol 35:3301-11
Kril, Liliia M; Vilchez, Valery; Jiang, Jieyun et al. (2015) N-Aryl benzenesulfonamide inhibitors of [3H]-thymidine incorporation and β-catenin signaling in human hepatocyte-derived Huh-7 carcinoma cells. Bioorg Med Chem Lett 25:3897-9
Yeo, Samuel Chao Ming; Sviripa, Vitaliy M; Huang, Meng et al. (2015) Analysis of trans-2,6-difluoro-4'-(N,N-dimethylamino)stilbene (DFS) in biological samples by liquid chromatography-tandem mass spectrometry: metabolite identification and pharmacokinetics. Anal Bioanal Chem 407:7319-32
Frasinyuk, Mykhaylo S; Bondarenko, Svitlana P; Sviripa, Vitaliy M et al. (2015) Development of 6H-Chromeno[3,4-c]pyrido[3',2':4,5]thieno[2,3-e]pyridazin-6-ones as Par-4 Secretagogues. Tetrahedron Lett 56:3382-3384
Frasinyuk, Mykhaylo S; Mrug, Galyna P; Bondarenko, Svitlana P et al. (2015) Application of Mannich bases to the synthesis of hydroxymethylated isoflavonoids as potential antineoplastic agents. Org Biomol Chem 13:11292-301
Frasinyuk, Mykhaylo S; Bondarenko, Svitlana P; Khilya, Volodymyr P et al. (2015) Synthesis and tautomerization of hydroxylated isoflavones bearing heterocyclic hemi-aminals. Org Biomol Chem 13:1053-67

Showing the most recent 10 out of 14 publications