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Published on: August 2, 2024
BI 2536 induces gasdermin E-dependent pyroptosis in ovarian cancer
Jianting Huo1,2, Yuhong Shen3, Yuchen Zhang1,2
1Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Background:
The frequent emergence of drug resistance to chemotherapy is a major obstacle for the treatment of ovarian cancer. There is a need for novel drugs to fulfill this challenge. Pyroptosis-inducing drugs can inhibit tumor growth. However, their roles in ovarian cancer have not been demonstrated.
Methods:
We tested the effectiveness of a novel drug, BI 2536, which we found in colorectal cancer. Cell proliferation, cell cycle, and drug-induced apoptosis and pyroptosis were tested. In vivo treatments were performed using a cell-derived xenograft model.
Results:
BI 2536 significantly inhibited the proliferation of ovarian cancer cells and induced cell cycle arrest at the G2/M phases. After BI 2536 treatment, DNA fragmentation and PS exposure on the outside of apoptotic cells were detected. Moreover, the pyroptotic phenotype of ovarian cancer cells along with the release of LDH and HMGB1 were observed, indicating the leakage of cells. Western blot analysis verified that BI 2536 induced GSDME-mediated pyroptosis. Pyroptosis was abolished after additional treatment with Z-DEVD-FMK, a caspase-3 inhibitor. Thus, BI 2536 induced pyroptosis in ovarian cancer through the caspase-3/GSDME pathway. In vivo experiments further demonstrated the antitumoral effect and ability of BI 2536 to accumulate CD8+ T cells in ovarian cancer.
Conclusion:
In this study, we identified BI 2536 as an effective anti-ovarian cancer drug that inhibits proliferation, arrests the cell cycle, induces apoptosis and pyroptosis, and leads to the accumulation of CD8+ T cells in tumor sites. Drug-induced pyroptosis may have promising prospects for reducing side effects and activating immune responses.
Insights
BI 2536 effectively combats ovarian cancer by inhibiting cell growth and inducing apoptosis and pyroptosis. This novel drug also enhances CD8+ T cell accumulation, offering a promising new avenue for ovarian cancer treatment.
Area of Science:
- Oncology
- Cancer Biology
- Drug Discovery
Background:
- Ovarian cancer treatment faces challenges due to frequent drug resistance to chemotherapy.
- Novel therapeutic strategies, including pyroptosis-inducing drugs, are needed to overcome resistance and improve outcomes.
- The potential of pyroptosis-inducing agents in ovarian cancer therapy remains largely unexplored.
Purpose of the Study:
- To investigate the efficacy of BI 2536, a novel drug identified in colorectal cancer, as a potential treatment for ovarian cancer.
- To evaluate the effects of BI 2536 on ovarian cancer cell proliferation, cell cycle progression, apoptosis, and pyroptosis.
- To assess the in vivo anti-tumoral activity and immune-modulating effects of BI 2536 in an ovarian cancer model.
Main Methods:
- In vitro assessment of BI 2536's impact on ovarian cancer cell proliferation and cell cycle.
- Analysis of drug-induced apoptosis and pyroptosis, including DNA fragmentation, PS exposure, LDH, and HMGB1 release.
- Western blot analysis to confirm the pyroptosis pathway (caspase-3/GSDME).
- In vivo studies using a cell-derived xenograft model to evaluate anti-tumoral effects and CD8+ T cell infiltration.
Main Results:
- BI 2536 significantly inhibited ovarian cancer cell proliferation and induced G2/M cell cycle arrest.
- The drug triggered apoptosis, evidenced by DNA fragmentation and PS exposure.
- BI 2536 induced GSDME-mediated pyroptosis, confirmed by LDH/HMGB1 release and caspase-3 inhibition experiments.
- In vivo studies demonstrated BI 2536's anti-tumoral efficacy and its ability to increase CD8+ T cell accumulation within tumors.
Conclusions:
- BI 2536 is identified as a potent anti-ovarian cancer agent, demonstrating anti-proliferative, cell cycle arrest, apoptosis, and pyroptosis-inducing properties.
- The drug facilitates CD8+ T cell infiltration into tumor sites, suggesting potential immunotherapeutic benefits.
- Drug-induced pyroptosis presents a promising strategy for ovarian cancer treatment, potentially reducing side effects and enhancing anti-tumor immune responses.
