Cell Line-Dependent Induction of Apoptosis and Cell Cycle Perturbation by Ixazomib in Glioblastoma Cells

Glioblastoma (GBM) remains one of the most aggressive primary brain tumors, with limited therapeutic options and a high rate of recurrence, highlighting the need for novel treatment strategies. Ixazomib (IXA), an orally bioavailable proteasome inhibitor, has demonstrated antitumor activity in preclinical models of GBM; however, the molecular mechanisms underlying its effects remain incompletely characterized. In the present study, we investigated the anti-glioblastoma activity of IXA with particular emphasis on apoptosis induction and cell cycle regulation across distinct GBM cell models. IXA treatment elicited substantial cytotoxic effects accompanied by activation of apoptotic signaling. Concurrent activation of caspase-8 and caspase-9 in several cell models indicated the involvement of both extrinsic and intrinsic apoptotic pathways. In parallel, IXA markedly altered cell cycle progression, although the nature and extent of these effects differed between cell lines, reflecting the molecular heterogeneity characteristic of GBM. These findings indicate that the cellular response to proteasome inhibition is strongly dependent on the molecular context of individual GBM models. Together with recent evidence demonstrating the proteasome dependence of recurrent GBM and the activity of IXA in patient-derived organoid and xenograft models, our results support further investigation of ixazomib as a potential therapeutic agent for GBM. In particular, elucidating cell-specific determinants of apoptotic and cell-cycle responses may facilitate the development of rational combination strategies aimed at enhancing the therapeutic efficacy of proteasome inhibition in glioblastoma.