{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T13:52:55Z","timestamp":1789912375162,"version":"4.0.1"},"reference-count":37,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2017,9,27]],"date-time":"2017-09-27T00:00:00Z","timestamp":1506470400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Malignant pleural mesothelioma (<jats:styled-content style=\"fixed-case\">MPM<\/jats:styled-content>), an asbestos\u2010related occupational disease, is an aggressive and incurable tumor of the thoracic cavity. Despite recent advances in <jats:styled-content style=\"fixed-case\">MPM<\/jats:styled-content> treatment, overall survival of patients with <jats:styled-content style=\"fixed-case\">MPM<\/jats:styled-content> is very low. Recent studies have implicated that <jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>3K\/Akt signaling is involved in <jats:styled-content style=\"fixed-case\">MPM<\/jats:styled-content> cell survival and development. To investigate the effects of Akt inhibitors on <jats:styled-content style=\"fixed-case\">MPM<\/jats:styled-content> cell survival, we examined the effects of nine selective Akt inhibitors, namely, afuresertib, Akti\u20101\/2, <jats:styled-content style=\"fixed-case\">AZD<\/jats:styled-content>5363, <jats:styled-content style=\"fixed-case\">GSK<\/jats:styled-content>690693, ipatasertib, <jats:styled-content style=\"fixed-case\">MK<\/jats:styled-content>\u20102206, perifosine, <jats:styled-content style=\"fixed-case\">PHT<\/jats:styled-content>\u2010427, and <jats:styled-content style=\"fixed-case\">TIC<\/jats:styled-content>10, on six <jats:styled-content style=\"fixed-case\">MPM<\/jats:styled-content> cell lines, namely, <jats:styled-content style=\"fixed-case\">ACC<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">MESO<\/jats:styled-content>\u20104, Y\u2010<jats:styled-content style=\"fixed-case\">MESO<\/jats:styled-content>\u20108A, <jats:styled-content style=\"fixed-case\">MSTO<\/jats:styled-content>\u2010211H, <jats:styled-content style=\"fixed-case\">NCI<\/jats:styled-content>\u2010H28, <jats:styled-content style=\"fixed-case\">NCI<\/jats:styled-content>\u2010H290, and <jats:styled-content style=\"fixed-case\">NCI<\/jats:styled-content>\u2010H2052, and a normal mesothelial cell line MeT\u20105A. Comparison of <jats:styled-content style=\"fixed-case\">IC<\/jats:styled-content><jats:sub>50<\/jats:sub> values of the Akt inhibitors showed that afuresertib, an <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>\u2010competitive specific Akt inhibitor, exerted tumor\u2010specific effects on <jats:styled-content style=\"fixed-case\">MPM<\/jats:styled-content> cells. Afuresertib significantly increased caspase\u20103 and caspase\u20107 activities and apoptotic cell number among <jats:styled-content style=\"fixed-case\">ACC<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">MESO<\/jats:styled-content>\u20104 and <jats:styled-content style=\"fixed-case\">MSTO<\/jats:styled-content>\u2010211H cells. Moreover, afuresertib strongly arrested the cell cycle in the G<jats:sub>1<\/jats:sub> phase. Western blotting analysis showed that afuresertib increased the expression of p21<jats:styled-content style=\"fixed-case\"><jats:sup>WAF<\/jats:sup><\/jats:styled-content><jats:sup>1\/<\/jats:sup><jats:styled-content style=\"fixed-case\"><jats:sup>CIP<\/jats:sup><\/jats:styled-content><jats:sup>1<\/jats:sup> and decreased the phosphorylation of Akt substrates, including <jats:styled-content style=\"fixed-case\">GSK<\/jats:styled-content>\u20103<jats:italic>\u03b2<\/jats:italic> and <jats:styled-content style=\"fixed-case\">FOXO<\/jats:styled-content> family proteins. These results suggest that afuresertib\u2010induced p21 expression promotes G<jats:sub>1<\/jats:sub> phase arrest by inducing <jats:styled-content style=\"fixed-case\">FOXO<\/jats:styled-content> activity. Furthermore, afuresertib significantly enhanced cisplatin\u2010induced cytotoxicity. Interestingly, results of gene set enrichment analysis showed that afuresertib modulated the expression <jats:italic>E2F1<\/jats:italic> and <jats:italic><jats:styled-content style=\"fixed-case\">MYC<\/jats:styled-content><\/jats:italic>, which are associated with fibroblast core serum response. Together, these results suggest that afuresertib is a useful anticancer drug for treating patients with <jats:styled-content style=\"fixed-case\">MPM<\/jats:styled-content>.<\/jats:p>","DOI":"10.1002\/cam4.1179","type":"journal-article","created":{"date-parts":[[2017,9,28]],"date-time":"2017-09-28T15:49:52Z","timestamp":1506613792000},"page":"2646-2659","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Novel ATP\u2010competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells"],"prefix":"10.1002","volume":"6","author":[{"given":"Masayuki","family":"Yamaji","sequence":"first","affiliation":[{"name":"Division of Chest Surgery Department of Surgery Aichi Medical University School of Medicine  Nagakute Aichi 480\u20101195 Japan"},{"name":"Department of Biochemistry Aichi Medical University School of Medicine  Nagakute Aichi 480\u20101195 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