title: Combined treatment with vitamin C and sulindac synergistically induces p53- and ROS-dependent apoptosis in human colon cancer cells.
abstract: Sulindac has anti-neoplastic properties against colorectal cancers; however, its use as a chemopreventive agent has been limited due to toxicity and efficacy concerns. Combinatorial treatment of colorectal cancers has been attempted to maximize anti-cancer efficacy with minimal side effects by administrating NSAIDs in combination with other inhibitory compounds or drugs such as l-ascorbic acid (vitamin C), which is known to exhibit cytotoxicity towards various cancer cells at high concentrations. In this study, we evaluated a combinatorial strategy utilizing sulindac and vitamin C. The death of HCT116 cells upon combination therapy occurred via a p53-mediated mechanism. The combination therapeutic resistance developed in isogenic p53 null HCT116 cells and siRNA-mediated p53 knockdown HCT116 cells, but the exogenous expression of p53 in p53 null isogenic cells resulted in the induction of cell death. In addition, we investigated an increased level of intracellular ROS (reactive oxygen species), which was preceded by p53 activation. The expression level of PUMA (p53-upregulated modulator of apoptosis), but not Bim, was significantly increased in HCT116 cells in response to the combination treatment. Taken together, our results demonstrate that combination therapy with sulindac and vitamin C could be a novel anti-cancer therapeutic strategy for p53 wild type colon cancers.
authors.affiliation: Asan Institute of Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
authors.forename: Eun-Yeung
authors.initials: EY
authors.lastname: Gong
authors.affiliation: Asan Institute of Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Shin
authors.affiliation: Asan Institute of Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
authors.forename: Ih-Yeon
authors.initials: IY
authors.lastname: Hwang
authors.affiliation: Asan Institute of Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
authors.forename: Jeong Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Asan Institute of Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; Division of Biosciences and Bioinformatics, Myongji University, 116 Myongji-ro, Cheoin-gu, Yongin, Gyeonggi-do 17058, Republic of Korea.
authors.forename: Seung-Mi
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Asan Institute of Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
authors.forename: Jai-Hee
authors.initials: JH
authors.lastname: Moon
authors.affiliation: Asan Institute of Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
authors.forename: Jae-Sik
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Asan Institute of Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
authors.forename: Dae-Hee
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Anatomy, Inje University College of Medicine, 75 Bokji-ro, Busanjin-gu, Busan 47392, Republic of Korea.
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Hur
authors.affiliation: Asan Institute of Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea.
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Jin
authors.affiliation: Asan Institute of Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; Department of Anatomy, Inje University College of Medicine, 75 Bokji-ro, Busanjin-gu, Busan 47392, Republic of Korea. Electronic address: choagene@amc.seoul.kr.
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Hong
authors.affiliation: Division of Biosciences and Bioinformatics, Myongji University, 116 Myongji-ro, Cheoin-gu, Yongin, Gyeonggi-do 17058, Republic of Korea. Electronic address: wklee@mju.ac.kr.
authors.forename: Won Keun
authors.initials: WK
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea.
authors.forename: Wang-Jae
authors.initials: WJ
authors.lastname: Lee
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D001205:Ascorbic Acid / Q000378:metabolism*; D002277:Carcinoma / Q000178:diet therapy / Q000188:drug therapy / Q000378:metabolism; D003110:Colonic Neoplasms / Q000178:diet therapy / Q000188:drug therapy* / Q000378:metabolism; D003131:Combined Modality Therapy; D019587:Dietary Supplements; D019008:Drug Resistance, Neoplasm; D018565:Food-Drug Interactions; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D009994:Osmolar Concentration; D016877:Oxidants / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000819:agonists* / Q000378:metabolism; D013467:Sulindac / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D016877:Oxidants; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D013467:Sulindac; D001205:Ascorbic Acid
keywords: Colon cancer; ROS; Sulindac; Vitamin C; p53