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The small-molecule compound BM-1197 inhibits the antiapoptotic regulators Bcl-2/Bcl-xL and triggers apoptotic cell death in human colorectal cancer cells

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Tumor Biology

Abstract

Small molecule BH3 mimetics comprise a promising new chemotherapeutic strategy for treating relapsed or chemoresistant cancer. In this study, we investigated the cellular mechanism of action by which BM-1197, a Bcl-xL/Bcl-2 dual inhibitor, triggers apoptosis in a panel of colorectal cancer (CRC) lines. Using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, we determined that BM-1197 inhibited CRC cell growth in a concentration- and time-dependent manner. The 50 % inhibitory concentration (IC50) values for the most sensitive cell lines, SW620 and SW480, ranged from 0.07 to 1.10 μM in response to a 72-h treatment. In CRC cells, BM-1197 induced apoptotic death without affecting the expression of Bcl-2 family proteins. However, BM-1197 effectively triggered a conformational change in Bax, releasing Bim from Bcl-xL by disrupting the interaction between Bcl-xL and Bak/Bax. Compared with the control group, BM-1197 treatment significantly increased the fraction of SW480 cells in the sub-G1 phase, the apoptosis rate, and cellular internucleosomal DNA fragmentation. The proapoptotic activity was associated with cytochrome c release, caspase-3 activation, and PARP-1 cleavage. Collectively, BM-1197 effectively suppressed the growth of the human CRC cell line SW480 by inducing mitochondria-dependent apoptotic cell death. These data have specific implications for the in vivo analysis and clinical evaluation of BM-1197 in CRC.

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (NSFC; no. 81101671).

Conflicts of interest

None

Author contributions

SL and JS designed the study. LY and GY wrote the manuscript. LY, FX, YS, and ZC performed the immunoblots, IPs, and related statistical analyses. MC, TL, and PS performed the cell culture and the MTT assays. All the authors approved the final version of the manuscript.

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Authors and Affiliations

  1. The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China

    Lijun Ye, Gang Yuan, Miaohong Chen, Tianxiao Li, Pingping Sun & Shuxia Li

  2. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China

    Fei Xu, Yueli Sun & Jian Sun

  3. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, People’s Republic of China

    Ziyan Chen

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  1. Lijun Ye
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  2. Gang Yuan
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  3. Fei Xu
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  4. Yueli Sun
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  5. Ziyan Chen
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  7. Tianxiao Li
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  9. Shuxia Li
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  10. Jian Sun
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Corresponding authors

Correspondence to Shuxia Li or Jian Sun.

Additional information

Lijun Ye and Gang Yuan contributed equally to this work.

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Ye, L., Yuan, G., Xu, F. et al. The small-molecule compound BM-1197 inhibits the antiapoptotic regulators Bcl-2/Bcl-xL and triggers apoptotic cell death in human colorectal cancer cells. Tumor Biol. 36, 3447–3455 (2015). https://doi.org/10.1007/s13277-014-2980-z

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  • DOI: https://doi.org/10.1007/s13277-014-2980-z

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