A novel bioavailable BH3 mimetic efficiently inhibits colon cancer via cascade effects of mitochondria
PUBLISHED: 2015-12-29  1541 total views, 1 today

Xuefeng Wang1Chen Zhang2Xiangming Yan3Bin Lan4Jianyong Wang3,Chongyang Wei3Xing Cao2Renxiao Wang2Jianhua Yao2Tao Zhou5Mi Zhou2,Qiaoling Liu3Biao Jiang2Pengfei Jiang6Santosh Kesari7Xinjian Lin8, and Fang Guo9,*

Author Affiliations 

1Key Laboratory of Tumor Targeted Therapy, Shanghai Advanced Research Institute, Chinese Academy of Sciences, University of Chinese Academy of Sciences
2CAS Key Laboratory of Synthetic Chemistry of Natural Substance, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences
3Laboratory of Tumor Targeted Therapy, Shanghai Advanced Research Institute, University of Chinese Academy of Sciences
4Chinese Academy of Sciences University, Shanghai Advanced Research Institute
5Academy of Life Science, Shanghai University
6Translational Neuro-Oncology Laboratories, UCSD Moores Cancer Center

7Neurosciences, UCSD Moores Cancer Center

8Moores UCSD Cancer Center, University of California, San Diego
9Key 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

*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.


Disclaimer: Only abstract of articles from non-members were published. This page aims to promote Chinese scientific research. There is no conflicts of interest with any journals reserved the copyright. For more please contact the author.



 




Author
Dr. Guo Fang
+ Author Profile

Dr Guo Fang

Director of Nano-medicine and translational medicinecenter, Shanghai Advanced Research Institute, Chinese Academy of Sciences.

Email: guofang@sibs.ac.cn


Research Area

  • Molecular mechanisms of tumor invasion and metastasis

  • Tumor-targeted drug development

  • Tumor gene vaccine and cellular vaccine development

 

Research Project

  • The mechanisms of Legumain actionin breast cancer metastasis.

  • In the hypoxia and acidicmicroenvironment of solid tumors, the compound of Legumain and integrin couldactivate Pro-MMP2 and Pro-Cathepsin L to promote tumor growth, invasion andmetastasis. Legumain was taken as a target to develop targeted small moleculeanticancer compound and anti-cancer prodrugs.

  • The role and mechanisms ofTumor-Associated Macrophages (TAMs) in promoting tumor metastasis and theimpact of Legumain on TAMs.

  • Osteoclasts play an importantrole in bone metastases from cancer, whereas legumain may interacted with TRAF6from RANKL \ RANK \ TRAF6 that is differentiation spindle of osteoclast.

  • Mouse models of Gelatin9KO(Lgals9), Mcl KO(Clec4d), Pomgnt1 KO(Pomgnt1) and DC-SIGN KO(Cd209a) weretaken to develop the impact of genes function on tumor growth and metastasis.

 


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