1. Academic Validation
  2. A novel Bcl-2 inhibitor, BM-1197, induces apoptosis in malignant lymphoma cells through the endogenous apoptotic pathway

A novel Bcl-2 inhibitor, BM-1197, induces apoptosis in malignant lymphoma cells through the endogenous apoptotic pathway

  • BMC Cancer. 2019 Dec 31;20(1):1. doi: 10.1186/s12885-019-6169-0.
Yue-Li Sun 1 Wen-Qi Jiang 2 3 Qiu-Yun Luo 2 4 Da-Jun Yang 2 4 Yu-Chen Cai 2 4 Hui-Qiang Huang 5 6 Jian Sun 7 8
Affiliations

Affiliations

  • 1 Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
  • 2 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 3 Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China.
  • 4 Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 5 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. huanghq@sysucc.org.cn.
  • 6 Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, China. huanghq@sysucc.org.cn.
  • 7 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. sunjian@sysucc.org.cn.
  • 8 Department of Clinical Research, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, China. sunjian@sysucc.org.cn.
Abstract

Background: Bcl-2 Family members play an important role in the development of malignant lymphoma and can induce drug resistance in Anticancer treatment. The development of small molecules targeting Bcl-2 Family proteins may be a new strategy for the treatment of malignant lymphoma. In this study, we investigate the antitumor effect and cellular mechanism of a novel Bcl-2/Bcl-xL dual inhibitor, BM-1197, in DCBCL and Burkitt lymphoma cells.

Methods: The CCK-8 assay was used to detect cell viability. Apoptosis was determined by Hoechst 33258 staining and flow cytometry. The activity of Caspase-3/caspase-9 was determined using a Caspase-3/caspase-9 activity kit. Western blotting analysis was performed to evaluate the changes in protein expression. Functional analysis was performed via immunoprecipitation and siRNA interference. Human malignant lymphoma xenograft models in nude mice were established for in vivo efficacy detection.

Results: We find that BM-1197 exerts potent growth-inhibitory activity against lymphoma cells that harbor high expression of Bcl-2 and Bcl-xL in vitro and has a synergistic effect with chemotherapeutic drugs. Mechanistically, we see that the intrinsic Apoptosis pathway is activated upon BM-1197 treatment. BM-1197 affects the protein interactions of Bak/Bcl-xL, Bim/Bcl-2, Bim/Bcl-xL, and PUMA/Bcl-2 and induces conformational changes in the Bax protein, which result in the activation of Bax and release of cytochrome c, activate Caspase - 9, - 3, and - 7 and finally induce cell Apoptosis. Furthermore, our data demonstrate that BM-1197 exhibits strong anti-tumor effects against established human malignant lymphoma xenograft models.

Conclusions: Our study demonstrated BM-1197 exerts potent antitumor effects both in vitro and in vivo and provides promising preclinical data for the further development of BM-1197 in malignant lymphoma.

Keywords

Apoptosis; Bcl-2 inhibitor; Chemotherapy; Malignant lymphoma; Targeted therapy.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-120882
    99.48%, Dual Bcl-2/Bcl-xL Inhibitor