title: Synergistic chemopreventive effects of nobiletin and atorvastatin on colon carcinogenesis.
abstract: Different cancer chemopreventive agents may act synergistically and their combination may produce enhanced protective effects against carcinogenesis than each individual agent alone. Herein, we investigated the chemopreventive effects of nobiletin (NBT, a citrus polymethoxyflavone) and atorvastatin (ATST, a lipid-lowering drug) in colon cancer cells/macrophages and an azoxymethane (AOM)-induced colon carcinogenesis rat model. The results demonstrated that co-treatments of NBT/ATST produced enhanced growth inhibitory and anti-inflammatory effects on the colon cancer cells and macrophages, respectively. Isobologram analysis confirmed that these interactions between NBT and ATST were synergistic. NBT/ATST co-treatment also synergistically induced extensive cell cycle arrest and apoptosis in colon cancer cells. Oral administration of NBT (0.1%, w/w in diet) or ATST (0.04%, w/w in diet) significantly decreased colonic tumor incidence and multiplicity in AOM-treated rats. Most importantly, co-treatment of NBT/ATST at their half doses (0.05% NBT + 0.02% ATST, w/w in diet) resulted in even stronger inhibitory effects on colonic tumor incidence and multiplicity than did NBT or ATST alone at higher doses. Statistical analysis confirmed that the enhanced chemopreventive activities against colon carcinogenesis in rats by the NBT/ATST combination were highly synergistic. Our results further demonstrated that NBT/ATST co-treatment profoundly modulated key cellular signaling regulators associated with inflammation, cell proliferation, cell cycle progression, apoptosis, angiogenesis and metastasis in the colon of AOM-treated rats. In conclusion, for the first time, our results demonstrated a strong synergy in inhibiting colon carcinogenesis produced by the co-treatment of NBT and ATST, which provided a scientific basis for using NBT in combination with ATST for colon cancer chemoprevention in humans.
authors.affiliation: Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: Xian
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA.|School of Pharmacy, Ocean University of China, Qingdao, Shandong 266003, People's Republic of China and.
authors.forename: Peiju
authors.initials: P
authors.lastname: Qiu
authors.affiliation: Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: Kanyasiri
authors.initials: K
authors.lastname: Rakariyatham
authors.affiliation: Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: Zili
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: Minqi
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA.|Institute of Agro-Products Processing Science and Technology, Chinese Academy of Agricultural Sciences, Beijing 100091, People's Republic of China.
authors.forename: Jinkai
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Xiao
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin / Q000494:pharmacology*; D001397:Azoxymethane / Q000494:pharmacology; D063646:Carcinogenesis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention / Q000379:methods; D003106:Colon / Q000187:drug effects* / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D047309:Flavones / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D016588:Anticarcinogenic Agents; D047309:Flavones; D000069059:Atorvastatin; C008661:nobiletin; D001397:Azoxymethane