Reversal of cisplatin resistance by inhibiting PI3K/Akt signal pathway in human lung cancer cells

Y. ZHANG, C. BAO, Q. MU, J. CHEN, J. WANG, Y. MI, A. J. SAYARI, Y. CHEN, M. GUO

Abstract:

Cisplatin is regularly used in the treatment of lung cancer. However, its efficacy is limited because of drug resistance. In this study, we found that Akt expression and activity was increased in lung cancer cells with acquired cisplatin resistance (A549/DDP cells and H460/DDP cells) when compared to their parental cells. Inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt kinase activity by its natural inhibitor, Wortmannin, could sensitize DDP-resistant cells to DDP and reverse DDP resistance. Combination treatment of Wortmannin with cisplatin is capable of increasing the mortality rate of both A549/DDP cells and H460/DDP cells. The present study also demonstrated that hyperactivation of PI3K/Aktpathway is closely associated with cisplatin resistance by regulating the Bax-mitochondria-mediated apoptosis pathway in human lung cancer. Inhibition of PI3K/Aktactivity in A549/DDP cells and H460/DDP cells could reverse cisplatin resistance by enhancing the effect of cisplatin on Bax oligomerization and release of Cytochrome C, allowing activation of the caspase-mediated apoptosis pathway. In conclusion, cisplatin resistance of lung cancer can be reversed via the inhibition of the PI3K/Akt signaling pathway. Therefore, both PI3K and Akt may be potential targets for overcoming cisplatin resistance in lung cancer.