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

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.

• Authors: Xuefeng Wang, Chen Zhang, Xiangming Yan, Bin Lan, Jianyong Wang, Chongyang Wei, Xingxin Cao, Renxiao Wang, Jianhua Yao, Tao Zhou, Mi Zhou, Qiaoling Liu, Biao Jiang, Pengfei Jiang, Santosh Kesari, Xinjian Lin, Fang Guo
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 6 Pg. 1445-58 (Mar 15 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 26515494 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Aniline Compounds
• Bax protein (53-86)
• Inhibitor of Apoptosis Proteins
• Organoplatinum Compounds
• Peptide Fragments
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• Oxaliplatin
• TOR Serine-Threonine Kinases
• Caspases
• navitoclax

Topics

• Aniline Compounds (pharmacology)
• Apoptosis (drug effects)
• Biological Mimicry
• Caspases (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Movement
• Cell Proliferation (drug effects)
• Cell Survival
• Colonic Neoplasms (metabolism, pathology)
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Mitochondria (drug effects, metabolism, ultrastructure)
• Mitophagy (drug effects)
• Models, Molecular
• Molecular Structure
• Organoplatinum Compounds (pharmacology)
• Oxaliplatin
• Peptide Fragments (chemistry, pharmacology)
• Protein Binding
• Protein Conformation
• Proto-Oncogene Proteins (chemistry, pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, chemistry, metabolism)
• Sulfonamides (pharmacology)
• TOR Serine-Threonine Kinases (metabolism)