American Association for Cancer Research
10780432ccr150732-sup-147327_2_supp_3139559_n8gt68.pptx (18.91 MB)

Supplementary Datas from A Novel Bioavailable BH3 Mimetic Efficiently Inhibits Colon Cancer via Cascade Effects of Mitochondria

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posted on 2023-03-31, 18:50 authored by 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

Supplemental Figure S1. 1H NMR spectrum and 13C spectrum of ch282-5. Supplemental Figure S2. LC/MS Report of ch282-5. Supplemental Figure S3. Synthesis profile of ch282-5 (2-aminoethanesulfonic acid sodium-gossypolone). Supplemental Table S1. The biological prediction of ch282-5. Supplemental Figure S4. Stability of ch282-5 in biological condition. Supplemental Figure S5. Binding affinities to Bcl-2 family proteins. Supplemental Table S2. Cell Viability Assay of ch282-5. Supplemental Figure S6. ch282-5 inhibits colon cancer cell ability. Supplemental Figure S7. ch282-5 regulates Bcl-2 family proteins. Supplemental Figure S8. ch282-5 antitumor ability is augmented by disturbing mitophagy and mTOR pathway. Supplemental Figure S9. ch282-5 suppresses liver colonization of colon cancer cells. Supplemental Figure S10. A schematic diagram of anti-colon cancer effects by ch282-5.



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. Clin Cancer Res; 22(6); 1445–58. ©2015 AACR.