Novel cilengitide derivatives suppress migration and invasion of temozolomide-resistant glioblastoma cells via MAPK/Akt pathway inhibition.

BACKGROUND: Temozolomide (TMZ) resistance and the invasive nature of glioblastoma (GBM) significantly limit therapeutic outcomes. Cilengitide, an RGD-containing integrin inhibitor, has shown anti-migratory effects, but its potential in TMZ-resistant GBM remains unclear. This study evaluated cilengitide and newly synthesized derivatives for their ability to inhibit migration and invasion in TMZ-resistant GBM cells. METHODS: T98G cells were treated with cilengitide and seven derivatives. Cell viability, apoptosis, migration, and invasion were assessed using 2D assays and 3D spheroid models. Gene expression was analyzed by qRT-PCR, and MAPK/Akt signaling was examined by Western blotting. Combination effects with the tyrosine kinase inhibitor dovitinib were evaluated using wound healing and invasion assays. RESULTS: Among the derivatives, R-1 and R-7 significantly reduced cell viability and induced PARP-1 cleavage, similar to cilengitide. Both peptides inhibited migration and invasion in a concentration-dependent manner and suppressed MMP2/MMP9 expression. R-1 primarily reduced Akt phosphorylation, whereas cilengitide and R-7 inhibited JNK activation. In 3D spheroids, cilengitide derivatives modestly affected viability but markedly impaired migratory capacity. Co-treatment with dovitinib produced a synergistic inhibition of migration and invasion compared with single-agent treatment. CONCLUSION: Cilengitide derivatives R-1 and R-7 effectively suppress migration and invasion of TMZ-resistant GBM cells through inhibition of MAPK/Akt signaling and matrix-degrading enzymes. Their synergistic interaction with dovitinib highlights the potential of peptide-based integrin antagonists as combination therapeutic candidates for overcoming TMZ resistance in GBM.