Abstract
Introduction: Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor, is characterized by a poor prognosis, with a median survival of only 12-18 months. This unfavorable outcome is largely attributed to severe resistance to temozolomide (TMZ), the standard chemotherapeutic agent used for treatment, which leads to treatment failure and tumor recurrence. Imipramine, a tricyclic antidepressant, has demonstrated potential as a modulator of signaling pathways. This study aimed to investigate the role of imipramine in increasing the sensitivity of U87MG glioblastoma cells to TMZ through the inhibition of the PI3K/Akt pathway.
Methods: In this experimental study, U87MG cells were treated with TMZ and imipramine, both as single agents and in combination. Cell survival and proliferation were assessed using the MTT assay. Gene expression levels of PI3K, Akt, Bax, Bcl-2, and Caspase-3 were measured via quantitative real-time polymerase chain reaction (qRT-PCR). Apoptosis rates were also measured using enzyme-linked immunosorbent assay (ELISA) and flow cytometry.
Results: Individually, TMZ and imipramine exerted inhibitory effects on cell proliferation. However, their combination significantly reduced the TMZ IC50 value from 78 to 35 µM. Combination treatment led to a significant downregulation of PI3K and Akt gene expression accompanied by upregulation of Bax and Caspase-3 and downregulation of Bcl-2 (P<0.05). The apoptosis rate in the combination group exceeded 82%, and the combination with a PI3K inhibitor increased this rate to 94%.
Conclusion: These results indicate that imipramine can effectively reverse intrinsic glioblastoma resistance to TMZ by concurrently inhibiting the PI3K/Akt pathway and activating the mitochondrial apoptosis pathway. Given the established safety profile of imipramine, its potential use as an adjuvant drug in the treatment of glioblastoma is significant and requires further investigation through animal models and subsequent clinical trials.