Antiproliferative effect of Aurora kinase targeting in mesothelioma

Our plain-English summary of Antiproliferative effect of Aurora kinase targeting in mesothelioma, by S. Crispi, C. Fagliarone, A. Biroccio, et al (Lung Cancer, 2010).

The study

• Authors: S. Crispi, C. Fagliarone, A. Biroccio, C. D'Angelo, R. Galati, A. Sacchi, B. Vincenzi, A. Baldi, A. Verdina
• Journal: Lung Cancer
• Published: 2010;70(3):271-9
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The Aurora proteins are a small family of serine/threonine kinase that function in various stages of mitosis. Current interest in Aurora kinase relates to its role in tumours, and its potential as a therapeutic target. In this work we studied the expression of Aurora kinases A and B and related genes in human mesothelioma tissues and in five mesothelioma cell lines. Moreover, we analyzed the effects of ZM447439 (ZM), an Aurora kinase inhibitor, on cellular growth. Results evidenced an over-expression of Aurora kinase A and related genes in human mesothelioma tissues and an over-expression of Aurora kinases A and B in all cell lines. Moreover, we demonstrated that ZM447439 was able to inhibit cell growth in all cell lines and that this inhibition was due to a specific effect as demonstrated by the reduction in the level of Histone H3 phosphorylation. Our findings support a role of Aurora kinase in mesothelioma and the possibility of using Aurora kinase inhibitors in therapeutic modalities.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

In plain English

This laboratory study examined Aurora kinases A and B, proteins involved in cell division, in malignant mesothelioma. It did not study asbestos exposure. The authors first reanalysed earlier gene-activity data from mesothelioma tumour samples. They reported higher expression of Aurora kinase A, and of most genes known to interact with Aurora kinases, in tumour than in normal tissue. They then stained tumour tissue from 29 patients treated at the Second University of Naples between 1980 and 1996. Aurora A was present in 17 of 29 samples and Aurora B in 19 of 29. Patients whose tumours lacked Aurora B had longer median survival than those whose tumours showed it. Aurora A showed no link with survival. Both kinases were found in five laboratory-grown mesothelioma cell lines. The Aurora kinase inhibitor ZM447439 slowed growth in all five, with IC50 values (the concentration giving half inhibition of growth) between 0.58 and 0.84 micromolar at 48 hours. The authors concluded that Aurora kinases, particularly Aurora B, are candidate treatment targets. They said further studies and future "in vivo" experiments are needed.

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 study: reanalysis of earlier tumour gene-expression data, immunohistochemical staining of archived mesothelioma tissue with a retrospective survival analysis, and experiments on mesothelioma cell lines
• Who was studied: Tumour tissue from 29 mesothelioma patients (16 epithelioid, 6 sarcomatoid, 7 mixed) treated at the Second University of Naples, Italy, between 1980 and 1996. Also five human mesothelioma cell lines (MSTO-211H, NCI-H2452, IstMes1, IstMes2, MPP89), compared with the prostate cancer cell line PC3.
• Exposure: No asbestos exposure was studied. In the cell experiments, the exposure was the Aurora kinase inhibitor ZM447439, tested at concentrations from 0.1 to 10 micromolar for up to 72 hours.
• Main results:
  • In the reanalysed gene-expression data, Aurora A and most genes known to interact with Aurora kinases showed higher expression in tumour than in normal tissue.
  • In the 29 tumour specimens, Aurora A was present in 17 of 29 (58.6%) and Aurora B in 19 of 29 (65.5%).
  • No statistically significant correlation was found between Aurora A or B expression and the histological type of mesothelioma.
  • Aurora A expression was not correlated with prognosis. Median survival was longer in patients whose tumours lacked Aurora B than in patients whose tumours showed nuclear Aurora B (p less than or equal to 0.0001).
  • Aurora kinases A and B were both highly expressed in all five mesothelioma cell lines.
  • ZM447439 significantly inhibited growth in all five cell lines at all doses at 48 and 72 hours. The exception was IstMes1 at the lowest dose (0.5 micromolar).
  • At 48 hours, the IC50 of ZM447439 was between 0.58 and 0.84 micromolar across the cell lines.
  • ZM447439 caused cleavage of PARP, a marker of programmed cell death, in MSTO cells from 24 hours onward, increasing with dose. No PARP cleavage was seen in MPP cells.
  • Phosphorylated histone H3 (a target of Aurora B) was significantly reduced in MSTO and MPP89 cells after 12 hours of ZM447439 treatment.
• The authors' conclusion: The authors concluded that Aurora kinases, in particular Aurora kinase B, are candidate therapeutic targets for treating malignant mesothelioma.
• Limitations the authors state:
  • The authors stated that further studies are needed to confirm Aurora kinase B as a prognostic factor for survival.
  • The authors stated that future "in vivo" experiments with Aurora kinase inhibitors are needed to confirm Aurora kinase inhibition as a valid approach to therapy.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma.

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