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

Autor: Masayuki Yamaji, Hiroyuki Konishi, Masayuki Haniuda, Sivasundaram Karnan, Akinobu Ota, Toshinori Hyodo, Shinobu Tsuzuki, Wahiduzzaman, Yoshitaka Hosokawa
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Mesothelioma
Cancer Research
Pathology
Benzylamines
Pyridines
FOXO1
Apoptosis
chemistry.chemical_compound
0302 clinical medicine
Phosphorylation
Original Research
Cancer Biology
Caspase 7
Oxadiazoles
Sulfonamides
Caspase 3
Forkhead Box Protein O1
Imidazoles
FOXO Family
Afuresertib
Cell cycle
Perifosine
Gene Expression Regulation
Neoplastic
Oncology
030220 oncology & carcinogenesis
cancer therapy
Heterocyclic Compounds
3-Ring
Cyclin-Dependent Kinase Inhibitor p21
medicine.medical_specialty
Phosphorylcholine
Pleural Neoplasms
Antineoplastic Agents
Thiophenes
Heterocyclic Compounds
4 or More Rings
03 medical and health sciences
Inhibitory Concentration 50
Cell Line
Tumor
Quinoxalines
Thiadiazoles
medicine
Humans
Radiology
Nuclear Medicine and imaging
Pyrroles
Akt inhibitor
Protein kinase B
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Glycogen Synthase Kinase 3 beta
business.industry
G1 Phase Cell Cycle Checkpoints
030104 developmental biology
Pyrimidines
chemistry
Cancer research
Pyrazoles
business
Proto-Oncogene Proteins c-akt
Zdroj: Cancer Medicine
ISSN: 2045-7634
Popis: 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 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 G1 phase. Western blotting analysis showed that afuresertib increased the expression of p21WAF 1/ CIP 1 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.
Databáze: OpenAIRE
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