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Melodinines J Induces Apoptosis in Temozolomide-Resistant Glioma Cells by Disrupting TMX1-Dependent Homeostasis of
Fanfan Chen1, Weiwei Cao2, Xuejuan Li3
1Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Futian District, Shenzhen, China.
Abstract:
Glioma is recognized as one of the most lethal and aggressive brain tumors. Although the standard-of-care treatment for glioblastoma (GBM) involves maximal surgical resection and temozolomide (TMZ) chemotherapy, the discovery of novel anti-tumor agents from nature sources is an effective strategy for glioma treatment. In this study, we conducted a screening process to identify the bisindole alkaloid melodinine J (MDJ) from Melodinus tenuicaudatus. We assessed its potency in overcoming TMZ resistance in patient-derived recurrent glioma strains, TMZ-resistant cell lines, and nude mouse tumor models of glioma cells. Our results first indicated that MDJ effectively inhibited malignancy and stimulated apoptosis in glioma. Mechanistic studies revealed that MDJ triggered deadly mitochondrial dysfunction and apoptosis by disrupting cross-organellar communication between the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs). We also showed that high levels of TMX1 may promote malignancy of glioma by ER-mitochondria communications, bioenergetics efficiency, and tumor growth. Overall, our study proved that MDJ interfered the function of TMX1-mediated MAM networks, thereby overcoming the proliferation and chemo-resistance of glioma cells.
Insights
Melodinine J (MDJ), a natural compound, effectively combats glioma by inducing apoptosis and overcoming temozolomide (TMZ) resistance. It disrupts endoplasmic reticulum-mitochondria communication, offering a novel therapeutic strategy for aggressive brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Natural Products Chemistry
Background:
- Glioma, particularly glioblastoma (GBM), is a highly lethal brain tumor with limited treatment options.
- Standard treatment involves surgery and temozolomide (TMZ) chemotherapy, but resistance remains a significant challenge.
- Exploring natural compounds offers a promising avenue for developing novel anti-glioma agents.
Purpose of the Study:
- To identify and evaluate the anti-glioma potential of melodinine J (MDJ), a bisindole alkaloid from Melodinus tenuicaudatus.
- To investigate MDJ's efficacy in overcoming temozolomide (TMZ) resistance in various glioma models.
- To elucidate the molecular mechanisms underlying MDJ's anti-tumor activity.
Main Methods:
- Screening of natural products to isolate MDJ.
- Assessment of MDJ's anti-proliferative and pro-apoptotic effects in patient-derived glioma strains and TMZ-resistant cell lines.
- Evaluation of MDJ in nude mouse tumor models.
- Mechanistic studies focusing on mitochondrial dysfunction and endoplasmic reticulum-mitochondria crosstalk.
Main Results:
- MDJ demonstrated significant inhibition of glioma malignancy and induced apoptosis.
- MDJ effectively overcame TMZ resistance in patient-derived and cell line models.
- Mechanistic studies revealed MDJ disrupts endoplasmic reticulum (ER)-mitochondria-associated membranes (MAMs) communication, leading to mitochondrial dysfunction.
- High TMX1 levels were implicated in promoting glioma malignancy via ER-mitochondria communication.
Conclusions:
- MDJ is a potent natural compound effective against glioma, including TMZ-resistant forms.
- MDJ exerts its anti-tumor effects by disrupting ER-mitochondria crosstalk and inducing apoptosis.
- MDJ represents a promising therapeutic candidate for overcoming glioma chemo-resistance and proliferation.
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