Beta-Diketone–Cobalt Complexes Sensitize Glioma Stem Cells to Temozolomide Partly Through the ERK-MGMT Pathway

Abstract

Glioblastoma multiforme is characterized by high invasiveness, multidrug resistance, and inevitable recurrence, and current standard treatment regimens are not curative. Even if most glioma cells are eliminated by chemotherapy and radiotherapy, glioma stem cells can survive and differentiate into new tumor cells, thereby triggering tumor recurrence and drug resistance. Therefore, inhibiting tumor invasiveness, reversing drug resistance, and effectively ablating glioma stem cells are critical for improving the prognosis of glioblastoma multiforme. Previous studies reported that the combination of β-diketone–cobalt complexes (CoAc2) and temozolomide (TMZ) has synergistic inhibitory effects on glioma cells. Therefore, we compared cell proliferation, colony-forming capacity, cell migration, and invasion of TMZ-resistant glioma cells and corresponding glioma stem cells after treatment with CoAc2 and/or TMZ. We also explored the underlying mechanism by which CoAc2 sensitizes cells to TMZ through transcriptome sequencing and related signal pathway blockade. We found that CoAc2 significantly increased the inhibitory effect of TMZ on the proliferation, colony formation, migration, invasion, and survival of drug-resistant stem cells. By downregulating ERK pathway activity, CoAc2 inhibited the expression of O6-methylguanine-DNA methyltransferase and eventually sensitized drug-resistant glioma cells to TMZ. In conclusion, the combined use of CoAc2 and TMZ can reverse TMZ resistance and significantly enhance its inhibitory effect on the malignant phenotype of glioma cells and glioma stem cells.