Crocetin: A Promising Adjunctive Therapy Enhancing Temozolomide Efficacy in Malignant Glioblastoma through Suppression of AKT, ERK, and p38 Signaling Pathways

Abstract Background Glioblastoma multiforme (GBM) is an aggressive brain tumor known for its invasive nature, presenting challenges in surgical resection. Crocetin and crocin, derived from saffron, exhibit potential as natural biomedicines, demonstrating cytotoxic and anticancer effects. Methods and results Although research on crocetin in glioma is limited, our study focused on its impact using the U87 cell line. Crocetin effectively suppressed glioma cell viability, proliferation, colony formation, migration, and invasion at concentrations of 75–150 µM. Mechanistically, it downregulated MMP-9 and RhoA mRNA expression, leading to reduced MMP-9 levels and inhibited F-actin polymerization. Additionally, crocetin dose-dependently inhibited AKT phosphorylation at Thr308 and Ser473, suppressing the AKT signaling pathway. Crocetin treatment significantly increased the subG1 and S-phase populations of U87 cells. Combined with TMZ, crocetin synergistically enhanced growth inhibition, potentially through increased apoptosis and suppressed cell replication. Co-treatment of crocetin with TMZ also reduced HMGB1 expression and concurrently decreased RAGE expression. Moreover, crocetin selectively inhibited ERK and p38 phosphorylation in the MAPK signaling pathway while leaving the JNK pathway unaffected. Conclusion In conclusion, our findings highlight crocetin's therapeutic potential for glioma treatment. It effectively targets multiple cellular processes involved in glioma progression by modulating MMP-9, RhoA, AKT, and HMGB1. Further research is needed to fully exploit crocetin's therapeutic benefits in glioma treatment.