Effect of doramectin on programmed cell death pathway in glioma cells
Songlin Du1, Hongsheng Liang2, Lu Zhou1
1Department of Biochemistry and Molecular Biology, College of Life Sciences, Northeast Agricultural University, Harbin, 150030, China.
Purpose:
Doramectin (DRM) is a kind of avermectin drugs, and it has been shown that DRM has anti-cancer effects. However, the molecular mechanism of DRM in programmed cell death (PCD) aspects is still unclear. The objective of this study was to confirm whether DRM induced PCD in glioma cells.
Methods:
In this experiment, the MTT assay and Ki-67 assay were used to detect in vitro cell viability and in vivo tumor proliferation. Then, the effect of DRM on PCD was analyzed by transcriptome comparison. Next, Endogenous apoptosis was detected by transmission electron microscopy (TEM), the DNA gel electrophoresis, JC-1 assay, western blotting and qRT-PCR. Meanwhile, necroptosis was detected by TEM, Hoechst 33342, FITC and PI staining assay, western blotting.
Results:
We found DRM induced apoptosis through Bcl-2/Bax/Caspase-3 pathway. And, DRM induced ROS overproduction, then ROS caused necroptosis through RIPK1/RIPK3/MLKL pathway, Mitochondria acted as a bridge between the two pathways.
Conclusion:
Our research provided new insight with the function of anti-cancer of DRM. These results demonstrated DRM may be used as potential therapeutic agents inducing apoptosis and necroptosis for cancer therapy.
Insights
Doramectin (DRM) triggers cancer cell death via apoptosis and necroptosis. This avermectin derivative shows promise as a novel anti-cancer therapeutic agent by activating specific molecular pathways.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Doramectin (DRM), an avermectin derivative, exhibits anti-cancer properties.
- The precise molecular mechanisms underlying DRM's effects on programmed cell death (PCD) remain largely unelucidated.
- Understanding DRM's role in PCD is crucial for its potential therapeutic applications in cancer.
Purpose of the Study:
- To investigate whether doramectin (DRM) induces programmed cell death (PCD) in glioma cells.
- To elucidate the molecular pathways involved in DRM-induced cell death.
- To explore the potential of DRM as an anti-cancer therapeutic agent.
Main Methods:
- Cell viability and proliferation assessed using MTT and Ki-67 assays.
- Transcriptome analysis to evaluate DRM's impact on PCD.
- Apoptosis detection via transmission electron microscopy (TEM), DNA gel electrophoresis, JC-1 assay, western blotting, and qRT-PCR.
- Necroptosis detection through TEM, Hoechst 33342, FITC, PI staining, and western blotting.
Main Results:
- DRM induces apoptosis mediated by the Bcl-2/Bax/Caspase-3 pathway.
- DRM triggers reactive oxygen species (ROS) overproduction, leading to necroptosis via the RIPK1/RIPK3/MLKL pathway.
- Mitochondria play a pivotal role, acting as a central mediator between apoptosis and necroptosis pathways.
Conclusions:
- DRM effectively induces both apoptosis and necroptosis in glioma cells.
- Mitochondria are key in linking DRM-induced apoptosis and necroptosis.
- DRM demonstrates potential as a therapeutic agent for cancer treatment by inducing multiple cell death pathways.
