PDK1 Inhibitor GSK-470 Exhibits Potent Anticancer Activity in a Pheochromocytoma PC12 Cell Tumor Model via Akt/mTOR Pathway.

Abstract

Phosphoinositide-Dependent Kinase 1 (PDK1) is now widely studied in malignant solid tumors. Researchers have previously revealed that targeting PDK1 is thought of as a promising anticancer treatment strategy. The aim of this study was designed to evaluate the anticancer activity of GSK-470, a novel and highly specific inhibitor of PDK1, in Pheochromocytoma (PCC) tumor model. PC12 cells were xenografted into nude mice to build PCC tumor model. Animals were treated with GSK-470 vs vehicle. Mean tumor volume was calculated and compared across groups. TUNEL was used to detect apoptosis. The effects of PDK1 inhibitor GSK-470 on activation of the Akt signaling and its downstream Akt/mTOR pathway in xenotransplant tumor tissues were examined by western bolt. The mean tumor volume in GSK-470 group was significantly less than that in control group. TUNEL results found that cell apoptosis was markedly increased in GSK-470 group compared with the control group. The western bolt analysis showed that the phosphorylation of Akt at threonine 308 was significantly reduced in GSK-470 group. Also, GSK-470 strongly inhibited phosphorylation of mTOR on Ser2448, a marker for mTORC1 activity, as well as phosphorylation of p70S6K, best characterized targets of mTOR. Our results showed that GSK-470 exhibited potent anticancer activity in PC12 tumor-bearing mice. Also, we found that this effect appeared to be mediated by the inhibition of the Akt/mTOR pathway. The present study once again provides new insights into the therapeutic effects of inhibiting PDK1 in the treatment of malignant PCC. Therefore, we propose that GSK-470 might be an effective therapeutic agent for the treatment of malignant PCC.