title: Diallyl Disulfide (DADS), a Constituent of Garlic, Inactivates NF-κB and Prevents Colitis-Induced Colorectal Cancer by Inhibiting GSK-3β.
abstract: There is a strong belief that garlic has medicinal properties and may even reduce the risk of developing certain cancers including those of the gastrointestinal tract. The chemopreventive effects of garlic may be attributed to the anti-inflammatory properties of the sulfur-containing constituents of garlic, which includes diallyl disulfide (DADS). Here, we demonstrate that DADS prevented colorectal tumorigenesis in a mouse model of colitis-induced colorectal cancer. Supplementation with 85 ppm of DADS (60 mg daily human equivalent dose) in the diet of FVB/N mice treated with chemical carcinogen azoxymethane (AOM) and colonic irritant dextran sodium sulfate (DSS) resulted in the reduction in tumor incidence, tumor number, and tumor burden by 21.54%, 47.3%, and 66.4%, respectively. Further analysis revealed that mice fed the DADS-supplemented diet resolved the initial DSS-induced inflammation faster than those on the control diet, preventing prolonged inflammation and cellular transformation. Subsequent mechanistic studies in vitro suggest that DADS chemopreventive effects are mediated through NF-κB signaling. When SW480 colorectal cancer cells were treated with DADS, NF-κB nuclear localization and activity were diminished. Interestingly, NF-κB suppression was found to be dependent on DADS inhibition of GSK-3β, a positive regulator of NF-κB. Inhibition of GSK-3β and loss of nuclear NF-κB activity were also observed in vivo in AOM/DSS-treated mice fed a diet supplemented with 85 ppm DADS. Our results indicate that DADS can prevent tumorigenesis by suppressing inflammation, a process largely involving GSK-3β inhibition and consequential reduction in NF-κB nuclear localization. Cancer Prev Res; 9(7); 607-15. ©2016 AACR.
authors.affiliation: Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland. Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
authors.forename: Shakir M
authors.initials: SM
authors.lastname: Saud
authors.affiliation: Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, Maryland. Department of Infectious Disease, Guang'anmen Hospital, Beijing, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Li
authors.affiliation: Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
authors.forename: Zane
authors.initials: Z
authors.lastname: Gray
authors.affiliation: Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Matthias S
authors.initials: MS
authors.lastname: Matter
authors.affiliation: Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Colburn
authors.affiliation: Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, Maryland. Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Young
authors.affiliation: Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland. yk47s@nih.gov.
authors.forename: Young S
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D063646:Carcinogenesis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000150:complications; D015179:Colorectal Neoplasms / Q000209:etiology / Q000473:pathology*; D004220:Disulfides / Q000494:pharmacology*; D005737:Garlic / Q000737:chemistry; D000071679:Glycogen Synthase Kinase 3 beta / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*
chemical_list: D000498:Allyl Compounds; D000972:Antineoplastic Agents, Phytogenic; D004220:Disulfides; D016328:NF-kappa B; D010936:Plant Extracts; C028009:diallyl disulfide; D000071679:Glycogen Synthase Kinase 3 beta