Synthetic oleanolic acid derivative, RTA-408, overcome in TMZ-resistant glioblastoma cells by inducing apoptosis and G1 cell cycle arrest

Glioblastoma is the most malignant primary brain tumor. It is characterized by high cellular heterogeneity, which contributes to its high chemoresistance and recurrence rate. To investigate the anticancer effect of RTA-408 on TMZ-resistant glioblastoma, we developed 2 TMZ-resistant cell lines, GBM841R and U-87MGR. Our findings revealed that RTA-408 (Omaveloxolone) effectively inhibited growth, induced cytotoxicity, and reduced colony formation in TMZ-resistant glioblastoma cells. RTA-408 treatment also induced dose-dependent cell cycle arrest, increasing the proportion of cells in the G1 phase while reducing that of those in the G2/M phase. Moreover, RTA-408 enhanced apoptosis and caspase-3 activation in TMZ-resistant cells. Next-generation sequencing revealed that RTA-408 modulated the expression of Nrf2-Keap1-ARE downstream genes in both TMZ-resistant and TMZ-sensitive glioblastoma cells. Western blot analysis revealed that RTA-408 modulated apoptosis-related protein expression and inhibited reactive oxygen species production, thereby reducing oxidative stress in TMZ-resistant glioblastoma cells. These findings indicate that RTA-408 is not only a promising alternative for TMZ-sensitive glioblastoma but also a first-line treatment option for TMZ-resistant glioblastoma.