title: Combination of metformin and VSL#3 additively suppresses western-style diet induced colon cancer in mice.
abstract: Western-style diet (WD) and dysbiosis are known to be associated with colonic inflammation, which contributes to carcinogenesis. Metformin (Met) exerts anti-inflammatory effects to induce AMP-activated protein kinase (AMPK), resulting in suppressed protein synthesis and reduced cell proliferation. Probiotic VSL#3 (V) modifies microbial composition. We investigated the chemopreventive mechanisms of Met and V in WD-induced colitis-associated colon carcinogenesis. Male BALB/c mice were randomly divided into five groups: a control diet (CD) group, WD group, WD+ Met (250mg/kg/day) group, WD+V (1.3 million bacteria/day) group, and WD+Met+V group. All mice were exposed to azoxymethane (10mg/kg) followed by 2% dextran sodium sulfate (DSS) for 7 days. Using HCT-116 human colon cancer cell line, expression of AMPK, extracellular signal-regulated kinase (ERK), cyclin D1, and Bcl-2 was investigated and cell cycle arrest was assessed. WD enhanced the severity of colitis and tumor growth compared with CD. The combination of Met and V significantly ameliorated colitis and tumor growth by inhibiting macrophage infiltration and maintaining epithelial integrity. In vitro assays showed that the combination therapy promoted late apoptosis by inhibiting cyclin D1 and Bcl-2 and activating pro-apoptotic ERK. A combination therapy with Met and V attenuates tumor growth in a mouse model of WD-induced colitic cancer, suggesting that this strategy could be useful for the chemoprevention of colon cancer.
authors.affiliation: Health Screening & Promotion Center, Seoul, Republic of Korea.
authors.forename: Eun-Ju
authors.initials: EJ
authors.lastname: Chung
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Eun-Ju
authors.initials: EJ
authors.lastname: Do
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea; Department of Medicine, University of Ulsan, College of Medicine, Seoul, Republic of Korea.
authors.forename: Sang-Yeob
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Eun A
authors.initials: EA
authors.lastname: Cho
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Dong-Hee
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Sehyung
authors.initials: S
authors.lastname: Pak
authors.affiliation: Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Sung Wook
authors.initials: SW
authors.lastname: Hwang
authors.affiliation: Health Screening & Promotion Center, Seoul, Republic of Korea.
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jeong-Sik
authors.initials: JS
authors.lastname: Byeon
authors.affiliation: Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Byong Duk
authors.initials: BD
authors.lastname: Ye
authors.affiliation: Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Sang Hyoung
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Suk-Kyun
authors.initials: SK
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea; Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: sjmyung@amc.seoul.kr.
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Myung
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000150:complications; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D019938:Cyclin D1 / Q000037:antagonists & inhibitors; D066273:Diet, Western / Q000009:adverse effects*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D019936:Probiotics / Q000494:pharmacology*
chemical_list: D019938:Cyclin D1; D008687:Metformin; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases
keywords: Chemoprevention; Colon cancer; Metformin; VSL#3; Western-style diet