Xuefeng Wang¹, Chen Zhang², Xiangming Yan³, Bin Lan⁴, Jianyong Wang³,Chongyang Wei³, Xing Cao², Renxiao Wang², Jianhua Yao², Tao Zhou⁵, Mi Zhou²,Qiaoling Liu³, Biao Jiang², Pengfei Jiang⁶, Santosh Kesari⁷, Xinjian Lin⁸, and Fang Guo^9,*

Author Affiliations 

*Corresponding Author:
Fang Guo, Key Laboratory of Tumor Targeted Therapy, Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Advanced Research Institute, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Haike Road 99, Zhangjiang Hi-Tech Park, Shanghai, 201210, China guof@sari.ac.cn

Abstract

Purpose: Gossypol and its analogs, through their ability to bind to and inactivate BH3 domain-containing anti-apoptotic 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 HPLC 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 model and experimental liver metastasis model. 

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 anti-apoptotic 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 downregulaton 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.

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