Cyclopamine sensitizes Glioblastoma cells to Temozolomide treatment through Sonic Hedgehog pathway

Abstract

AimGlioblastoma is an extremely aggressive glioma, resistant to radio and chemotherapy usually performed with temozolomide. One of the main reasons for glioblastoma resistance to conventional therapies is due to the presence of cancer stem-like cells. These cells could recapitulate some signaling pathways important for embryonic development, such as Sonic hedgehog. Here, we investigated if the inhibitor of the Sonic hedgehog pathway, cyclopamine, could potentiate the temozolomide effect in cancer stem-like cells and glioblastoma cell lines in vitro.Main methodsThe viability of glioblastoma cells exposed to cyclopamine and temozolomide treatment was evaluated by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay while the induction of apoptosis was assessed by western blot. The stemness properties of glioma cells were verified by clonogenic and differentiation assay and the expression of stem cell markers were measured by fluorescence microscopy and western blot.Key findingsThe glioblastoma viability was reduced by cyclopamine treatment. Cyclopamine potentiated temozolomide treatment in glioblastoma cell lines by inducing apoptosis through activation of caspase-3 cleaved. Conversely, the combined treatment of cyclopamine and temozolomide potentiated the stemness properties of glioblastoma cells by inducing the expression of SOX-2 and OCT-4.SignificanceCyclopamine plays an effect on glioblastoma cell lines but also sensibilize them to temozolomide treatment. Thus, first-line treatment with Sonic hedgehog inhibitor followed by temozolomide could be used as a new therapeutic strategy for glioblastoma patients.

Hedgehog signaling regulates the development and treatment of glioblastoma (Review)

“…However, the combination of acepromazine and TMZ enhanced the dryness and drug resistance of GBM cells by inducing the expression of SOX-2 and OCT-4 and may lead to tumor recurrence in patients (134). Therefore, the best therapeutic strategy is to first inhibit the SHH pathway and then administer TMZ (134,135). Liu et al (136) found that the combination of capsulated propylamine and TMZ had synergistic cytotoxic effects and was more likely to inhibit the ability to induce apoptosis and eliminate neuroglobin formation by inhibiting GLI1 expression.…”