Multikinase inhibitor motesanib enhances the antitumor effect of cisplatin in cisplatin‑resistant human bladder cancer cells via apoptosis and the PI3K/Akt pathway

Abstract

Motesanib (AMG 706) is a small organic molecule that acts as a multi-targeted tyrosine kinase inhibitor of VEGF, PDGF and stem cell factor receptor. It exhibits a potent antitumor effect in vitro and in vivo. To investigate the anticancer effect and possible mechanisms of motesanib in cisplatin-resistant human bladder cancer cells (T24R2), T24R2 cells were treated with motesanib (50 µM) with or without cisplatin (2.5 µg/ml). Cell growth was assessed by the Cell Counting Kit-8 and clonogenic assays. Cell cycle progression and apoptotic cell death were examined using flow cytom-etry. The expression levels of apoptosis- and survival-related proteins were determined by western blot analysis. In combination with cisplatin, motesanib exhibited synergistic inhibition on T24R2 cell growth. Treatment using motesanib in combination with cisplatin markedly induced apoptosis and promoted cell cycle arrest in the S phase. It also increased the expression of apoptosis-related genes including caspases, poly(ADP-ribose) polymerase and cytochrome c, whereas it decreased the expression of survival-related genes including p-PI3K and p-Akt. In conclusion, combination treatment with motesanib and cisplatin revealed a synergistically enhanced anticancer effect on cisplatin-resistant human bladder cancer cells, accompanied with induced apoptosis and cell cycle arrest. Thus, the multikinase inhibitor motesanib could be developed as possible therapeutic agent for bladder cancer.