Investigation of the anti-angiogenic effects of antidepressant drug imipramine on glioblastoma cell line

Date

2024-12-06

Author

Çabuk, Deniz

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Imipramine is a tricyclic antidepressant used in the treatment of certain psychiatric disorders by inhibiting the reuptake of norepinephrine and serotonin at presynaptic nerve terminals. The potential direct or indirect effects of tricyclic antidepressants on various types of cancer have been observed in both in vitro and in vivo studies. Although the exact pathways involved in these effects remain uncertain, multiple potential mechanisms have been identified. These mechanisms primarily include pathways that play a role in cell proliferation and those regulating programmed cell death (apoptosis). Repurposing existing drugs, such as the antidepressant imipramine, offers a promising approach to targeting angiogenesis in glioblastoma. Glioblastoma is an aggressive brain tumor characterized by high angiogenic activity, primarily driven by vascular endothelial growth factor A (VEGFA). In this thesis, the effects of antidepressant drug imipramine on viability, VEGFA gene and protein expression, and VEGFA secretion in human glioblastoma cell lines, T98-G. The Alamar Blue assay revealed a dose- and time-dependent reduction in cell viability, with 100 μM imipramine for 48 hours being the optimal condition for further experiments. Quantitative real-time PCR demonstrated significant downregulation of VEGFA gene expression following imipramine treatment. However, western blot analysis showed no significant changes in VEGFA protein expression, and ELISA revealed no significant differences in secreted VEGFA levels between treated and control groups. These findings suggest that imipramine reduces VEGFA transcription but does not significantly impact translation or secretion, likely due to compensatory mechanisms or post-transcriptional regulation. This study highlights imipramine’s potential to disrupt glioblastoma angiogenesis at the transcriptional level but underscores the complexity of targeting angiogenic pathways in tumor cells. While imipramine shows promise as part of a multimodal therapeutic strategy, further research is needed to validate these findings in vivo, explore its effects on alternative angiogenic pathways, and evaluate its combinatory potential with other anti-cancer agents. The study contributes to the growing body of evidence supporting drug repurposing as a cost-effective strategy for glioblastoma treatment.

Subject Keywords

Glioblastoma, Angiogenesis, VEGF, Antidepressant, Imipramine

URI

https://hdl.handle.net/11511/112961

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Graduate School of Natural and Applied Sciences, Thesis