Curcumin sensitizes glioblastoma to temozolomide by simultaneously generating ROS and disrupting AKT/mTOR signaling

Abstract

Temozolomide (TMZ), a DNA alkylating agent, represents the most important chemotherapeutic option for the treatment of glioblastoma in the clinic. Despite its frequent use, the therapeutic efficacy of TMZ remains very limited due to its frequent resistance in glioblastoma. Previous evidence suggested that curcumin (CUM), an ingredient of the Indian spice turmeric, is able to sensitize glioblastoma to TMZ treatment. However, the underlying molecular mechanism remains elusive. In the present study, we performed in vitro and in vivo experiments to evaluate the interaction of CUM and TMZ on the inhibition of glioblastoma and to investigate its potential mechanisms of action using U87MG cell lines and xenograft mouse models. We demonstrated that CUM enhanced the therapeutic response to TMZ in U87MG glioblastoma by enhancing apoptosis. We then proceeded to investigate the potential apoptotic signaling pathways that are involved. We observed a synergistic effect of the combination of CUM and TMZ in generating reactive oxygen species (ROS) production, suggesting that ROS may contribute to the impact of CUM on sensitizing TMZ treatment. We also showed that CUM and TMZ treatment alone significantly suppressed phosphorylated AKT and mTOR, whereas their combination achieved a more pronounced inhibitory effect. These data indicated that blockage of AKT/mTOR signaling appeared to contribute to the elevated apoptosis caused by the combination treatment with CUM and TMZ. In conclusion, this study provided molecular insights into the effects of CUM on the therapeutic response of glioblastoma to TMZ and opened new avenues for optimizing the therapeutic effects of TMZ-based therapies.

Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function

“…Moreover, the cell protective autophagy has been reported to contribute to TMZ-induced cell death (40). The production of ROS and the disruption of AKT/mTOR signal have been demonstrated to contribute to the TMZ resistance (41). In this study, we focused on the contribution of TMZ-inducible ROS upregulation and the maintainable cysteine pool and GSH synthesis by xCT transporting and transsulfuration pathway in the resistance to TMZ (Fig.…”

The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent update

“…Curcumin sensitizes the glioblastoma to temozolomide by simultaneously generating ROS and inhibiting Akt/mTOR signalling pathway (Yin et al, 2014). It also inhibits beta-amyloid (Aβ) aggregation and induces autophagy by down-regulating PI3K/Akt/mTOR signaling pathway.…”

MicroRNA-144 represses gliomas progression and elevates susceptibility to Temozolomide by targeting CAV2 and FGF7

“…As the most effective medicine for malignant gliomas, the cytotoxicity of TMZ induced glioma cells apoptosis and activated multiple signaling pathway increasing glioma cells damages [43][44][45] . It has been reported that TMZ promoted ROS production in glioma tissues [46][47][48] . Our results indicated miR-144 had no effect on glioma cells apoptosis without other treatment.…”