A Novel Bioavailable BH3 Mimetic Efficiently Inhibits Colon Cancer via Cascade Effects of Mitochondria.

Jianhua Yao, Fang Guo, Xinjian Lin, Santosh Kesari, Pengfei Jiang, Biao Jiang, Qiaoling Liu, Mi Zhou, Tao Zhou, Xuefeng Wang, Renxiao Wang, Xingxin Cao, Chongyang Wei, Jianyong Wang, Bin Lan, Xiangming Yan, Chen Zhang

Journal: Clinical cancer research : an official journal of the American Association for Cancer Research 2016;22(6):1445-58

PMID: 26515494

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Abstract

PURPOSE

Gossypol and its analogs, through their ability to bind to and inactivate BH3 domain-containing antiapoptotic proteins, have been shown to inhibit the growth of various human cancer cells in culture and xenograft models. Here, we evaluated the antitumor efficacy of a novel gossypol derivative and BH3 mimetic ch282-5 (2-aminoethanesulfonic acid sodium-gossypolone) in colon cancer models. Several innovative combination strategies were also explored and elaborated.

EXPERIMENTAL DESIGN

Ch282-5 was synthesized by modifying the active aldehyde groups and R groups of gossypol according to a computer-aided drug design program. The stability of ch282-5 was examined by high-performance liquid chromatography, and cytotoxic effects of ch282-5 on colon cancer cells were assessed by MTS assay. Activation of mitochondrial apoptotic pathway by ch282-5 was evidenced with a series of molecular biology techniques. In vivo antitumor activity of ch282-5 and its combination with chloroquine, rapamycin, oxaliplatin, and ABT-263 was also evaluated in colon cancer xenograft models and experimental liver metastasis models.

RESULTS

Ch282-5 showed antiproliferative and pro-cell death activity against colon cancer cells both in vitro and in vivo, and the response to the drug correlated with inhibition of antiapoptotic Bcl-2 proteins, induction of mitochondria-dependent apoptotic pathway, and disruption of mitophagy and mTOR pathway. Ch282-5 also suppressed liver metastasis produced by intrasplenic injection of colon cancer cells. Furthermore, ch282-5 could potentiate the effectiveness of oxaliplatin and rescue ABT-263 efficacy by downregulation of Mcl-1 and elevation of platelet number.

CONCLUSIONS

These findings provide a rational basis for clinical investigation of this highly promising BH3 mimetic in colon cancer.

Address: Laboratory of Tumor Targeted Therapy, Shanghai Advanced Research Institute, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.; CAS Key Laboratory of Synthetic Chemistry of Natural Substance, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, China.; Laboratory of Tumor Targeted Therapy, Shanghai Advanced Research Institute, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.; Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China. Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.; Academy of Life Science, Shanghai University, Shanghai, China.; Department of Medicine and UC San Diego Moores Cancer Center, University of California-San Diego, La Jolla, California.; Department of Medicine and UC San Diego Moores Cancer Center, University of California-San Diego, La Jolla, California. [email protected] [email protected].; Laboratory of Tumor Targeted Therapy, Shanghai Advanced Research Institute, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China. [email protected] [email protected].

DOI: 10.1158/1078-0432.CCR-15-0732

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MeSH Terms: Aniline Compounds, Apoptosis, Biological Mimicry, Caspases, Cell Cycle Checkpoints, Cell Movement, Cell Proliferation, Cell Survival, Colonic Neoplasms, Humans, Inhibitor of Apoptosis Proteins, Mitochondria, Mitophagy, Models, Molecular, Molecular Structure, Organoplatinum Compounds, Oxaliplatin, Peptide Fragments, Protein Binding, Protein Conformation, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Sulfonamides, TOR Serine-Threonine Kinases