title: Cilostazol and enzymatically modified isoquercitrin attenuate experimental colitis and colon cancer in mice by inhibiting cell proliferation and inflammation.
abstract: We previously reported the anti-inflammatory effects of cilostazol, a selective inhibitor of phosphodiesterase 3, and two antioxidants, enzymatically modified isoquercitrin and α-lipoic acid in a dextran sodium sulphate-induced colitis mouse model. We further examined the chemopreventive effects of these substances in a murine azoxymethane/dextran sodium sulphate -induced colorectal carcinoma model and compared the effects with those of the well-known anticancer natural plant pigment, anthocyanin. In addition, the effects on cell proliferation activity were evaluated in colon cancer cell lines and mucosal epithelial cells in a model of acute dextran sodium sulphate-induced colitis. Cilostazol and enzymatically modified isoquercitrin improved the outcome of azoxymethane/dextran sodium sulphate-induced colorectal cancer along with anthocyanin though inhibiting inflammation and cell proliferation, but the effect of α-lipoic acid was minimal. Inhibition of cell proliferation by cilostazol was confirmed in vitro. In the acute dextran sodium sulphate-induced colitis model, cilostazol and enzymatically modified isoquercitrin prevented the decrease in epithelial proliferative cells. These results indicate that cilostazol and enzymatically modified isoquercitrin first exhibited an anti-dextran sodium sulphate effect at the initial stage of colitis and then showed antitumour effects throughout subsequent inflammation-related cancer developmental stages.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Pharmacokinetics and Safety Research Department, Drug Research Center, Kaken Pharmaceutical Co., Ltd., 301 Gensuke, Fujieda, Shizuoka 426-8646, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kangawa
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan. Electronic address: yoshida7@cc.tuat.ac.jp.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Pharmacokinetics and Safety Research Department, Drug Research Center, Kaken Pharmaceutical Co., Ltd., 301 Gensuke, Fujieda, Shizuoka 426-8646, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Pharmacokinetics and Safety Research Department, Drug Research Center, Kaken Pharmaceutical Co., Ltd., 301 Gensuke, Fujieda, Shizuoka 426-8646, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: Pharmacokinetics and Safety Research Department, Drug Research Center, Kaken Pharmaceutical Co., Ltd., 301 Gensuke, Fujieda, Shizuoka 426-8646, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kihara
authors.affiliation: Pharmacokinetics and Safety Research Department, Drug Research Center, Kaken Pharmaceutical Co., Ltd., 301 Gensuke, Fujieda, Shizuoka 426-8646, Japan.
authors.forename: Michi
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Animal Experimentation, Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, 5-1-1, Tsukiji, Tokyo 104-0045, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Ochiai
authors.affiliation: Department of Animal Experimentation, Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, 5-1-1, Tsukiji, Tokyo 104-0045, Japan; Division of Molecular Carcinogenesis, Chiba Cancer Center Research Institute, 666-2, Nitona-cho, Chuo-ku, Chiba-city, Chiba 260-8717, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hippo
authors.affiliation: Global Scientific and Regulatory Affairs, San-Ei Gen F. F. I., Inc., 1-1-11 Sanwa-cho, Toyonaka, Osaka 561-8588, Japan.
authors.forename: Shim-Mo
authors.initials: SM
authors.lastname: Hayashi
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects*; D000077407:Cilostazol; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size / Q000187:drug effects; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D002273:Carcinogens; D013777:Tetrazoles; D014665:Vasodilator Agents; C016527:isoquercitrin; D011794:Quercetin; D001397:Azoxymethane; D000077407:Cilostazol
keywords: Cilostazol; Colorectal cancer; Enzymatically modified isoquercitrin; Murine azoxymethane/dextran sodium sulphate-induced colorectal carcinoma model; Reactive oxygen species