Oroxylin A reversed Fibronectin-induced glioma insensitivity to Temozolomide by suppressing IPR1/AKT/β-catenin pathway.

Aims: Cell adhesion mediated-drug resistance (CAM-DR) is one of main reasons for. the limitation to chemotherapy, but the underlying mechanism remains unclear in glioma. In this study, we investigated the mechanism of CAM-DR induced by Fibronectin (Fn). Besides, we studied the reversal effect of Oroxylin A, a natural flavonoid extracted from Scutellaria radix, on Temozolomide (TMZ) insensitivity of glioma cells.

Main Methods: Human Fn protein was used to mimic cell adhesion model and investigate its effect on the insensitivity of glioma cells to TMZ. Moreover, Oroxylin A was studied regarding its reversal effect on TMZ insensitivity of glioma via multiple molecular biological methods such as MTT, cell apoptosis assay, siRNA transfection, western blot, immunofluorescence assay.

Key Findings: Fn could decrease the apoptosis-inducing effect of TMZ and led to the CAM-DR in glioma cells. Further studies showed that up-regulations of IPR1 and intracellular Ca level induced the activation of AKT kinase which increased the phosphorylation of GSK-3β and subsequently caused the entry of β-catenin into the nucleus. Knocking down IPR1 significantly improved the sensitivity of glioma cells to TMZ. Meanwhile, after treatment with low-toxic concentration of Oroxylin A, the apoptosis induced by TMZ under Fn condition increased dramatically. Furthermore, our results revealed that Oroxylin A markedly inhibited the expression of IPR1 and the activation of AKT/β-catenin pathway.

Significance: Oroxylin A could reverse the insensitivity of TMZ via suppressing IPR1/AKT/β-catenin pathway and it might be helpful for enhancing the anti-cancer effect of TMZ in glioma.