Tumor Biology

, Volume 36, Issue 5, pp 3447–3455 | Cite as

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

  • Lijun Ye
  • Gang Yuan
  • Fei Xu
  • Yueli Sun
  • Ziyan Chen
  • Miaohong Chen
  • Tianxiao Li
  • Pingping Sun
  • Shuxia Li
  • Jian Sun
Research Article

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.

Keywords

BM-1197 BH3 mimetic Colorectal cancer Apoptosis Bcl-2 

Notes

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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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Lijun Ye
    • 1
  • Gang Yuan
    • 1
  • Fei Xu
    • 2
  • Yueli Sun
    • 2
  • Ziyan Chen
    • 3
  • Miaohong Chen
    • 1
  • Tianxiao Li
    • 1
  • Pingping Sun
    • 1
  • Shuxia Li
    • 1
  • Jian Sun
    • 2
  1. 1.The First Affiliated HospitalSun Yat-sen UniversityGuangzhouPeople’s Republic of China
  2. 2.State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhouPeople’s Republic of China
  3. 3.State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangzhouPeople’s Republic of China

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