Donafenib suppresses glioblastoma progression: potential enhancement of therapeutic response in TMZ-resistant models.

Glioblastoma (GBM) is the most aggressive primary brain tumor of the central nervous system and remains largely incurable due to the development of resistance to temozolomide (TMZ). Aberrant activation of growth factor-mediated signaling pathways, including VEGFR and MET, plays a critical role in GBM progression, highlighting the need for alternative therapeutic strategies. Donafenib (DNF) is a novel multikinase inhibitor targeting VEGFR, PDGFR, and RAF signaling pathways. In this study, we evaluated the effects of DNF on proliferation-associated signaling pathways in U87MG and T98G GBM cell lines. DNF treatment significantly reduced cell viability, colony formation, migration, and invasion. Moreover, immunocytochemical analyses revealed lower levels of immunoreactivity for several markers associated with tumor progression, including p-ERK, NF-κB p65, p-mTOR, p-MET, p-STAT3, and p-VEGFR, following DNF treatment. While PAMPA analysis indicated that DNF exhibits lower blood-brain barrier (BBB) permeability than TMZ, in silico modeling revealed that a substantial proportion of its metabolites may possess BBB-penetrating potential. Collectively, these findings suggest that DNF exerts antitumor effects in both TMZ-sensitive and TMZ-resistant GBM models and highlight its potential as a promising therapeutic candidate for further investigation.