Nitidine Chloride Is a Potential Alternative Therapy for Glioma Through Inducing Endoplasmic Reticulum Stress and
Zihang Chen1,2,3, Jinsen Zhang2,3,4, Hao Xue1,2,3
1Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.
Abstract:
Background: Malignant glioma is a lethal brain tumor that is highly resistant to standard therapy. Our research aims to explore the suppressive effects of nitidine chloride (NC) on gliomas and the mechanisms involved, showing that it is a potential agent for integrative therapy of gliomas. Methods: After glioma cells were treated with NC, several experiments were performed to evaluate NC's antitumor effects. CCK-8 assay was used to detect viability. Transwell and 3-dimensional spheroid invasion assays were used to evaluate motility of glioma in vitro, and the sphere-formation assay showed NC's influence on glioma stem cells. Apoptosis and intracellular reactive oxygen species were measured by means of flow cytometry. Subcellular structures were observed through transmission electron microscopy. Western blot analysis reflected expression of endoplasmic reticulum (ER) stress and epithelial-mesenchymal transition (EMT) marker proteins. An orthotopic xenograft model was established to investigate the tumor suppressive effects in vivo. Results: Nitidine chloride inhibited glioma cell migration and invasion in vitro, downregulated the EMT proteins, and suppressed sphere formation of glioma stem cells. Furthermore, NC induced persistent ER stress that contributed to apoptosis and reactive oxygen species production. The xenograft model showed that NC effectively restricted glioma growth and invasion in vivo. Furthermore, we confirmed the signaling pathways that ER stress downregulates C/EBPβ and slug, as well as inhibition of the AKT/GSK3β/β-catenin axis caused by NC, in U-87 MG. Conclusion: We demonstrated that NC inhibits gliomas in vitro and in vivo by activating ER stress and downregulating EMT, which provides a basis for glioma therapy.
Insights
Nitidine chloride (NC) effectively suppresses malignant glioma growth and invasion by activating endoplasmic reticulum (ER) stress and downregulating epithelial-mesenchymal transition (EMT). This research highlights NC as a promising agent for integrated glioma therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Malignant glioma presents a significant therapeutic challenge due to its resistance to conventional treatments.
- Identifying novel therapeutic agents is crucial for improving outcomes in glioma patients.
Purpose of the Study:
- To investigate the antitumor effects of nitidine chloride (NC) on malignant gliomas.
- To elucidate the underlying mechanisms of NC's action, focusing on endoplasmic reticulum (ER) stress and epithelial-mesenchymal transition (EMT).
Main Methods:
- In vitro assays (CCK-8, Transwell, 3D spheroid invasion, sphere formation) assessed glioma cell viability, motility, and stem cell properties.
- Flow cytometry measured apoptosis and reactive oxygen species (ROS).
- Western blot analyzed ER stress and EMT markers; an orthotopic xenograft model evaluated in vivo efficacy.
Main Results:
- Nitidine chloride inhibited glioma cell migration, invasion, and sphere formation in vitro.
- NC induced persistent ER stress, leading to apoptosis and increased ROS production.
- In vivo studies demonstrated that NC restricted glioma growth and invasion.
Conclusions:
- Nitidine chloride exhibits potent anti-glioma activity both in vitro and in vivo.
- NC functions by activating ER stress and downregulating EMT pathways.
- These findings support NC as a potential therapeutic agent for integrative glioma therapy.
