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Trichodermin exhibits potent anti-glioblastoma activity by inducing cell cycle arrest and apoptosis, suppressing
Hung-Pei Tsai1,2, Tzong-Huei Lee3, Hong-Liang Lin4
1Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Abstract:
Trichodermin, a sesquiterpene antibiotic from Trichoderma species, shows anticancer potential. In this study, anti-glioblastoma activity was evaluated by (3-(4,5-di methyl thiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay, colony formation, lactate dehydrogenase (LDH) release assay, flow cytometry, wound-healing, transwell invasion, adhesion, Western blot, combination-index analysis, and an orthotopic luciferase glioblastoma mouse model. Trichodermin reduced viability and clonogenicity and increased LDH release of T98G and A172 cells. Trichodermin induced G2/M arrest with p53 activation and downregulation of cyclin B, cyclin A, and cyclin-dependent kinase 1 (CDK1). In addition, trichodermin induced caspase-dependent apoptosis. Invasion, wound healing, and adhesion were suppressed with modulation of epithelial-mesenchymal transition (EMT)-related proteins. Combination index analysis demonstrated a synergistic interaction between trichodermin and temozolomide, possibly due to increased apoptosis. In the mouse model, intraperitoneal trichodermin inhibited intracranial tumour growth and prolonged survival, and increased cleaved caspase-3 expression in tumour tissues. These findings indicate that trichodermin exerts anti-glioblastoma activity and warrants further preclinical evaluation as a potential adjunct to temozolomide therapy.
Insights
Trichodermin, an anticancer compound, effectively reduced glioblastoma cell growth and tumor progression in mice. It shows promise as a potential combination therapy with temozolomide for glioblastoma treatment.
Area of Science:
- Natural Products Chemistry
- Cancer Biology
- Pharmacology
Background:
- Glioblastoma is an aggressive brain tumor with limited treatment options.
- Trichodermin, a sesquiterpene from Trichoderma species, exhibits anticancer properties.
- Exploring novel therapeutic agents for glioblastoma is crucial.
Purpose of the Study:
- To evaluate the anti-glioblastoma activity of trichodermin.
- To investigate the mechanisms underlying trichodermin's effects.
- To assess trichodermin's efficacy in combination with temozolomide and in an in vivo model.
Main Methods:
- Cell viability (MTT assay), clonogenicity, and LDH release assays.
- Flow cytometry for cell cycle analysis and apoptosis.
- Western blotting for protein expression (p53, cyclins, CDK1, EMT markers, cleaved caspase-3).
- In vitro invasion, wound healing, and adhesion assays.
- Combination-index analysis with temozolomide.
- Orthotopic luciferase glioblastoma mouse model.
Main Results:
- Trichodermin reduced glioblastoma cell viability, clonogenicity, invasion, migration, and adhesion.
- It induced G2/M cell cycle arrest, p53 activation, and caspase-dependent apoptosis.
- Trichodermin modulated epithelial-mesenchymal transition (EMT) markers.
- Synergistic effects were observed when combined with temozolomide.
- In vivo, trichodermin inhibited tumor growth and prolonged survival in mice.
Conclusions:
- Trichodermin demonstrates significant anti-glioblastoma activity through multiple mechanisms.
- It shows potential as an adjunct therapy to temozolomide.
- Further preclinical studies are warranted to explore trichodermin for glioblastoma treatment.
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