2. Academic Validation
  3. Combined treatment with vitamin C and sulindac synergistically induces p53- and ROS-dependent apoptosis in human colon cancer cells

Combined treatment with vitamin C and sulindac synergistically induces p53- and ROS-dependent apoptosis in human colon cancer cells

  • Toxicol Lett. 2016 Sep 6;258:126-133. doi: 10.1016/j.toxlet.2016.06.019.
Eun-Yeung Gong 1,  Yu Jin Shin 1,  Ih-Yeon Hwang 1,  Jeong Hee Kim 1,  Seung-Mi Kim 2,  Jai-Hee Moon 1,  Jae-Sik Shin 1,  Dae-Hee Lee 1,  Dae Young Hur 3,  Dong-Hoon Jin 1,  Seung-Woo Hong 4,  Won Keun Lee 5,  Wang-Jae Lee 6
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Anatomy, Inje University College of Medicine, 75 Bokji-ro, Busanjin-gu, Busan 47392, Republic of Korea.
  • 4 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.
  • 5 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.
  • 6 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.
PMID: 27339904 DOI: 10.1016/j.toxlet.2016.06.019
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.

Keywords

Colon cancer; ROS; Sulindac; Vitamin C; p53.

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