Reference Detail

Ref Type

Journal Article

PMID

(26515494)

Authors

Wang X, Zhang C, Yan X, Lan B, Wang J, Wei C, Cao X, Wang R, Yao J, Zhou T, Zhou M, Liu Q, Jiang B, Jiang P, Kesari S, Lin X, Guo F

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	22	6	2016 Mar 15	1445-58	Clin Cancer Res

URL

Abstract Text

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

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Ch282-5	Ch282-5	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Ch282-5			BCL2 Family Inhibitor 6	Ch282-5 is a gossypol derivative that binds to and inhibits BCL2, family proteins, resulting in decreased tumor cell growth and increased sensitivity to chemotherapeutic agents (PMID: 26515494, PMID: 29885833).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References