Effects of an oral allosteric AKT inhibitor (MK-2206) on human nasopharyngeal cancer?in?vitro and in vivo

摘要

Aim: Protein kinase B (AKT) signaling frequently is deregulated in human cancers and plays an important role in nasopharyngeal carcinoma (NPC). This preclinical study investigated the effect of MK-2206, a potent allosteric AKT inhibitor, on human NPC cells in vitro and in vivo. Methods: The effect of MK-2206?on the growth and proliferation of CNE-1, CNE-2, HONE-1, and SUNE-1?cells was assessed by Cell Counting Kit 8?and colony formation assay. Flow cytometry was performed to analyze cell cycle and apoptosis. The effects of MK-2206?on the AKT pathway were analyzed by Western blotting. Autophagy induction was evaluated via electron microscopy and Western blot. To test the effects of MK-2206?in vivo, CNE-2?cells were subcutaneously implanted into nude mice. Tumor-bearing mice were treated orally with MK-2206?or placebo. Tumors were harvested for immunohistochemical analysis. Results: In vitro, MK-2206?inhibited the four NPC cell line growths and reduced the sizes of the colonies in a dose-dependent manner. At 72?and 96?hours, the half maximal inhibitory concentration (IC50) values of MK-2206?in CNE-1, CNE-2, and HONE-1?cell lines were 3–5?μM, whereas in SUNE-1, IC50?was less than 1?μM, and MK-2206?induced cell cycle arrest at the G1?phase. However, our study found no evidence of apoptosis. MK-2206?induced autophagy in NPC cells, as evidenced by electron microscopy and Western blot, and inhibited the growth of tumors that were subcutaneously implanted in mice. Inhibition of downstream phosphorylation through the PRAS40?and S6?pathways seems to be the main mechanism for the MK-2206-induced growth inhibition.Conclusion: Our preclinical study suggests that MK-2206’s antiproliferative effect may be useful for NPC treatment; however, strategies for reinforcing this effect are needed to maximize clinical benefit.