Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells

Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.

Abstract

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 PI3K/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, AZD5363, GSK690693, ipatasertib, MK-2206, perifosine, PHT-427, and TIC10, 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 IC50 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 G1 phase. Western blotting analysis showed that afuresertib increased the expression of p21WAF1/CIP1 and decreased the phosphorylation of Akt substrates, including GSK-3β and FOXO family proteins. These results suggest that afuresertib-induced p21 expression promotes G1 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.

Keywords: Afuresertib; Akt inhibitor; Mesothelioma; cancer therapy.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Benzylamines / pharmacology
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Forkhead Box Protein O1 / metabolism
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Humans
  • Imidazoles
  • Inhibitory Concentration 50
  • Mesothelioma / drug therapy*
  • Oxadiazoles / pharmacology
  • Phosphorylation / drug effects
  • Phosphorylcholine / analogs & derivatives
  • Phosphorylcholine / pharmacology
  • Pleural Neoplasms / drug therapy*
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrazoles / pharmacology*
  • Pyridines
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • Quinoxalines / pharmacology
  • Sulfonamides / pharmacology
  • Thiadiazoles / pharmacology
  • Thiophenes / pharmacology*

Substances

  • 4-dodecyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide
  • Akt-I-1,2 compound
  • Antineoplastic Agents
  • Benzylamines
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Forkhead Box Protein O1
  • GSK690693
  • Heterocyclic Compounds, 3-Ring
  • Heterocyclic Compounds, 4 or More Rings
  • Imidazoles
  • MK 2206
  • Oxadiazoles
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Pyrimidines
  • Pyrroles
  • Quinoxalines
  • Sulfonamides
  • Thiadiazoles
  • Thiophenes
  • Phosphorylcholine
  • perifosine
  • afuresertib
  • TIC10 compound
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Caspase 3
  • Caspase 7
  • capivasertib