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

Our plain-English summary of Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells, by M. Yamaji, A. Ota, M. Wahiduzzaman, et al (Cancer Medicine, 2017).

The study

• Authors: M. Yamaji, A. Ota, M. Wahiduzzaman, S. Karnan, T. Hyodo, H. Konishi, S. Tsuzuki, Y. Hosokawa, M. Haniuda
• Journal: Cancer Medicine
• Published: 2017;6(11):2646-2659
• Cited by: 48 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

In plain English

This was a laboratory study of cells grown in dishes, not of patients, and it did not study asbestos exposure. The authors, at Aichi Medical University in Japan, tested nine drugs that block a protein called Akt. They used six cell lines from malignant pleural mesothelioma and one normal mesothelial cell line, MeT-5A. Afuresertib and ipatasertib (also called GDC-0068) needed lower doses to reduce the survival of all six mesothelioma lines than of the normal line. For afuresertib, the dose that halved cell survival was 4.2 to 12.1 micromoles per litre in the mesothelioma lines, compared with 17.8 in MeT-5A. In further tests, mostly on two mesothelioma lines, afuresertib reduced colony formation, increased programmed cell death (apoptosis), stopped cell division at an early stage and reduced cell migration. Combined with the chemotherapy drug cisplatin, it reduced cell survival more than either drug alone. The authors concluded that afuresertib decreased mesothelioma cell survival by inhibiting Akt and may offer a combination option with cisplatin. They said it still needs testing in living animals.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study of cultured cell lines
• Who was studied: Six human malignant pleural mesothelioma cell lines (ACC-MESO-4, MSTO-211H, NCI-H2052, NCI-H28, NCI-H290, Y-MESO-8A) and one immortalized normal mesothelial cell line (MeT-5A), studied at Aichi Medical University, Japan; no patients were studied
• Exposure: Nine Akt-inhibiting drugs (afuresertib, Akti-1/2, AZD5363, GSK690693, ipatasertib, MK-2206, perifosine, PHT-427, TIC10), plus a PI3K inhibitor and a PDPK1 inhibitor, and afuresertib combined with cisplatin or pemetrexed; asbestos exposure was not studied
• Main results:
  • Afuresertib and ipatasertib (GDC-0068) had lower IC50 values (dose that halves cell survival) against all six mesothelioma cell lines than against the normal MeT-5A line. Afuresertib values were 4.2 to 12.1 µM in the mesothelioma lines versus 17.8 µM in MeT-5A (Table 2).
  • Afuresertib significantly inhibited colony formation by ACC-MESO-4 and MSTO-211H cells (P < 0.005) and by NCI-H2052 cells (P < 0.05)
  • Perifosine, but not afuresertib, significantly decreased colony numbers of the normal mesothelial MeT-5A cells
  • Afuresertib significantly increased the percentage of apoptotic cells in ACC-MESO-4 and MSTO-211H cells after 48 h. It significantly increased caspase-3 and caspase-7 activity in ACC-MESO-4 cells and only slightly increased it in MSTO-211H cells.
  • Afuresertib increased the share of cells in the G0/G1 phase and decreased the share in the S and G2-M phases of the cell cycle
  • Afuresertib combined with cisplatin significantly reduced the viability of ACC-MESO-4 and MSTO-211H cells compared with either drug alone
  • Afuresertib (5 µmol/L) suppressed migration of the mesothelioma cells in a scratch assay
  • In gene expression analysis, afuresertib raised the expression of 262 genes by more than 2.0-fold and lowered the expression of 219 genes to less than 0.5-fold compared with untreated cells
• The authors' conclusion: The authors concluded that afuresertib decreased the survival of malignant pleural mesothelioma cells by inhibiting Akt. They said that its enhancement of cisplatin's effects suggests afuresertib plus cisplatin as an option for treating the disease.
• Limitations the authors state:
  • The data came mainly from laboratory cell studies, and the drug's anticancer activity still needs to be tested in living animals, for example in xenograft models

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Occupational Disease, Overall Survival, Mesothelial Cells, Cisplatin, Fibroblast.

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