The total flavonoid of eucommia ulmoides sensitizes human glioblastoma cells to radiotherapy via HIF-α/MMP-2 pathway and activates intrinsic apoptosis pathway

Abstract

Background: As one of the most common and lethal malignant primary brain tumors, glioblastomas (GBMs) are identified as grade IV neoplasms, the most severe grade, according to WHO classification systems. The outcome of surgery against GBMs is limited since its frequent relapse. Radiotherapy is a crucial and widely used treatment after surgery, while the strong radioresistance of GBM cells still becomes a severe problem of radiotherapy. Eucommia ulmoides Oliv. is used for the treatment of various diseases, such as lower blood pressure and inflammation. Purpose: To explore the anti-tumor effect of Eucommia ulmoides Oliv. against GBMs. Methods: Dose-viability assays were performed to examine the anti-tumor effect. Wouldhealing and transwell assays were carried out to evaluate the migration and invasion ability of GBMs. Cell apoptosis was detected by 33, 258 staining, and the expressions of key proteins were examined by western blot. Results: In this study, we confirmed that the inhibitory effect of the total flavonoid of Eucommia ulmoides on proliferation, migration and invasion of human GBM cells. Its favorable effects inspired us to explore the potential ability in enhancing radiosensitivity of GBM cells. The results demonstrated that it could further induce apoptosis during radiotherapy via intrinsic apoptosis pathway. Besides, it could significantly reduce the malondialdehyde level after radiotherapy, which suggested it inhibited tumor cell and protected normal neuronal cells. By examining the expression of important genes of radioresistant pathway, we found a significant decrease of HIF-α/MMP-2 when using the total flavonoid of Eucommia ulmoides during radiotherapy. Conclusion: This result suggests that the enhancement of radiotherapy may be mediated by modulating glucose metabolism of GBMs in HIF-α/MMP-2 pathway.