Cinnamophilin enhances temozolomide-induced cytotoxicity against malignant glioma: The roles of ROS and cell cycle arrest

Background: Temozolomide (TMZ) has been widely used to treat glioblastoma multiforme (GBM). However, many mechanisms are known to quickly adapt GBM cells to chemotherapy with TMZ, leading to drug resistance and expansion of tumor cell populations. Methods: We subjected human glioblastoma cell lines and an animal model of glioblastoma xenografts with TMZ-based adjuvant treatments to evaluate the synergistic effect of cinnamophilin (CINN), a free radical scavenger. Results: Our results showed that the combined treatment of CINN and TMZ potentiated the anticancer effect and apoptotic cell death in glioma cell lines and enhanced antitumor action in glioma xenografts. TMZ induced reactive oxygen species (ROS) burst and elevated G2 arrest in glioma cells. The CINN-suppressed ROS burst in TMZ-treated glioma cells might be associated with increased apoptosis, as indicated by the upregulation of TUNEL-positive glioma cells. CINN-pretreated glioma cells exhibited increased cyclin B expression and reduced phosphorylation of Cdk1, suggesting reduced G2 arrest in the combined treatment group. Moreover, CINN lowered the protein level of LC3, a hallmark of autophagy, in TMZ-treated cells. Conclusions: These findings suggest that CINN may restore TMZ toxicity in glioma cancer by suppressing the ROS/G2 arrest pathway.