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.