Open AccessNovel ATP‐competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells
Author(s) -
Yamaji Masayuki,
Ota Akinobu,
Wahiduzzaman Md,
Karnan Sivasundaram,
Hyodo Toshinori,
Konishi Hiroyuki,
Tsuzuki Shinobu,
Hosokawa Yoshitaka,
Haniuda Masayuki
Publication year - 2017
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1179
Subject(s) - protein kinase b , mesothelioma , cancer research , cell culture , apoptosis , cell growth , chemistry , phosphorylation , medicine , biology , microbiology and biotechnology , pathology , biochemistry , genetics
Malignant pleural mesothelioma ( MPM ), an asbestos‐related occupational disease, is an aggressive and incurable tumor of the thoracic cavity. Despite recent advances in MPM treatment, overall survival of patients with MPM is very low. Recent studies have implicated that PI 3K/Akt signaling is involved in MPM cell survival and development. To investigate the effects of Akt inhibitors on MPM cell survival, we examined the effects of nine selective Akt inhibitors, namely, afuresertib, Akti‐1/2, AZD 5363, GSK 690693, ipatasertib, MK ‐2206, perifosine, PHT ‐427, and TIC 10, on six MPM cell lines, namely, ACC ‐ MESO ‐4, Y‐ MESO ‐8A, MSTO ‐211H, NCI ‐H28, NCI ‐H290, and NCI ‐H2052, and a normal mesothelial cell line MeT‐5A. Comparison of IC 50 values of the Akt inhibitors showed that afuresertib, an ATP ‐competitive specific Akt inhibitor, exerted tumor‐specific effects on MPM cells. Afuresertib significantly increased caspase‐3 and caspase‐7 activities and apoptotic cell number among ACC ‐ MESO ‐4 and MSTO ‐211H cells. Moreover, afuresertib strongly arrested the cell cycle in the G 1 phase. Western blotting analysis showed that afuresertib increased the expression of p21 WAF 1/ CIP 1 and decreased the phosphorylation of Akt substrates, including GSK ‐3 β and FOXO family proteins. These results suggest that afuresertib‐induced p21 expression promotes G 1 phase arrest by inducing FOXO activity. Furthermore, afuresertib significantly enhanced cisplatin‐induced cytotoxicity. Interestingly, results of gene set enrichment analysis showed that afuresertib modulated the expression E2F1 and MYC , which are associated with fibroblast core serum response. Together, these results suggest that afuresertib is a useful anticancer drug for treating patients with MPM .