Additive effect of Ruta graveolens bioactive phytoconstituents and cisplatin through PKC/MEK/ERK pathway in glioblastoma

Glioblastoma multiforme (GBM) is a lethal malignancy with limited therapeutic options. Its aggressive progression and resistance to standard therapy necessitate the development of novel therapeutic strategies. Plant-based compounds have emerged as promising candidates for therapeutic development modulating key targets in cancer. The Ruta graveolens displays anti-inflammatory, analgesic, and antimicrobial properties. Herein, we report the anticancer potential of R. graveolens water extract (RGWE) on long-term cultures of human glioblastoma and elucidate the regulatory mechanisms driving its effect. Secondary stabilized cell cultures (U-87 MG, T98MG, and U-138 MG) and primary cell culture (FCN, MZC, and GL18-15) were either treated with RGWE and/or cis-diamminedichloroplatinum (cisplatin, CDDP). Cytostatic responses were assessed by cell viability (TB exclusion test), cell cycle (propidium iodide [PI] staining), and apoptosis (Annex-V and caspase-3) assays. We demonstrate that RGWE slows U-87 MG growth without affecting apoptosis and arrests the cell cycle in the G2/M phase. Mechanistically, RGWE interferes with PKC/MEK/ERK signaling pathway, as assessed by western blot analysis, through PKC inhibition in its active form. Furthermore, the combination of RGWE and cisplatin enables the use of a sublethal dose of the latter (0.2 μg/mL), thereby reducing cytotoxicity and the resistance to the drug. These findings reveal a novel mechanism by which RGWE controls glioblastoma growth, highlighting the therapeutic potential of targeting the PKC/MEK/ERK axis in glioma treatment.