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

• Main Authors: Zhao YY, Tian Y, Zhang J, Xu F, Yang YP, Huang Y, Zhao HY, Zhang JW, Xue C, Lam MH, Yan L, Hu ZH, Dinglin XX, Zhang L
• Format: Article
• Language: English
• Published: Dove Medical Press 2014-10-01
• Series: Drug Design, Development and Therapy
• Online Access: http://www.dovepress.com/effects-of-an-oral-allosteric-akt-inhibitor-mk-2206-on-human-nasophary-peer-reviewed-article-DDDT

Yuan-Yuan Zhao,1,* Ying Tian,1,* Jing Zhang,2,* Fei Xu,1 Yun-Peng Yang,1 Yan Huang,1 Hong-Yun Zhao,3 Jian-Wei Zhang,4 Cong Xue,1 Michael H Lam,5 Li Yan,5 Zhi-Huang Hu,1 Xiao-Xiao Dinglin,6 Li Zhang1,3 1Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 2Department of Medical Oncology, the First Affiliated Hospital of Guang Zhou Traditional Chinese Medicine University, Guangzhou, People’s Republic of China; 3National Anti-Cancer Drug Research Centre, Sun Yat-Sen University Cancer Center; State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 4The Six Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China; 5Merck and Co Inc, North Wales, PA USA; 6Sun Yat-Sen Memorial Hospital, Guangzhou, People’s Republic of China *These authors contributed equally to this work 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. Keywords: AKT inhibitor, MK-2206, nasopharyngeal carcinoma