Melodinines J Induces Apoptosis in Temozolomide-Resistant Glioma Cells by Disrupting TMX1-Dependent Homeostasis of Endoplasmic Reticulum-Mitochondria-Associated Membrane Contacts.

in Phytotherapy research : PTR by Fanfan Chen, Weiwei Cao, Xuejuan Li, Zebin Chen, Guoxu Ma, Sicen Wang, Zongyang Li, Lei Chen, Weiping Li, Xiangbao Meng, Guodong Huang, Ping Cui

TLDR

  • Bisindole alkaloid melodinine J (MDJ) was identified as an anti-tumor agent for glioblastoma treatment, overcoming TMZ resistance by disrupting ER-MAM communication.

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.

Overview

  • Main focus: Identify bisindole alkaloid melodinine J (MDJ) as an anti-tumor agent for glioblastoma (GBM) treatment.
  • Hypothesis: MDJ overcomes TMZ resistance in patient-derived recurrent glioma strains, TMZ-resistant cell lines, and nude mouse tumor models of glioma cells.
  • Methodology: Screening process to identify MDJ from Melodinus tenuicaudatus, and assessment of its potency in vitro and in vivo assays.

Comparative Analysis & Findings

  • MDJ inhibited malignancy and stimulated apoptosis in glioma cells in vitro and in vivo, indicating its anti-tumor activity.
  • Mechanistic studies showed that MDJ triggered mitochondrial dysfunction and apoptosis by disrupting ER-MAM communication.
  • High levels of TMX1 promoted malignancy of glioma by ER-MAM communications, bioenergetics efficiency, and tumor growth.

Implications and Future Directions

  • MDJ is a potential anti-tumor agent for overcoming TMZ resistance in glioblastoma treatment.
  • Future studies should investigate the detailed mechanism of MDJ-mediated apoptosis and mitochondrial dysfunction.
  • Further preclinical and clinical trials are needed to validate the efficacy and safety of MDJ in glioma treatment.
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