Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma

Our plain-English summary of Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma, by A. Baldi, M.T. Piccolo, M.R. Boccellino, et al (PloS One, 2011).

The study

• Authors: A. Baldi, M.T. Piccolo, M.R. Boccellino, A. Donizetti, I. Cardillo, R. La Porta, L. Quagliuolo, E.P. Spugnini, F. Cordero, G. Citro, M. Menegozzo, R.A. Calogero, S. Crispi
• Journal: PloS One
• Published: 2011;6(8):e23569
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant mesothelioma (MM) is a rare, highly aggressive tumor, associated to asbestos exposure. To date no chemotherapy regimen for MM has proven to be definitively curative, and new therapies for MM treatment need to be developed. We have previously shown in vivo that piroxicam/cisplatin combined treatment in MM, specifically acts on cell cycle regulation triggering apoptosis, with survival increase.

Methodology/principal Findings: We analyzed, at molecular level, the apoptotic increase caused by piroxicam/cisplatin treatment in MM cell lines. By means of genome wide analyses, we analyzed transcriptional gene deregulation both after the single piroxicam or cisplatin and the combined treatment. Here we show that apoptotic increase following combined treatment is mediated by p21, since apoptotic increase in piroxicam/cisplatin combined treatment is abolished upon p21 silencing.

Conclusions/significance: Piroxicam/cisplatin combined treatment determines an apoptosis increase in MM cells, which is dependent on the p21 expression. The results provided suggest that piroxicam/cisplatin combination might be tested in clinical settings in tumor specimens that express p21.

In plain English

This laboratory study used human mesothelioma cells grown in culture, not patients. The authors treated MSTO-211H cells with the anti-inflammatory drug piroxicam, the chemotherapy drug cisplatin, or both. After 24 hours, cisplatin alone produced a 14% apoptotic induction (apoptosis is programmed cell death), and the combination produced a 33% apoptosis increase compared with untreated cells. No apoptotic induction was detected at 8 hours with either single or combined treatment. The NCI and Mes1 cell lines responded similarly, but no significant apoptosis was detected in Mes2 cells. Gene-activity analysis found 536 differentially expressed probe sets, including increased activity of the gene for p21, a cell-cycle protein, after the combination. Total p21 protein did not rise and was noticed to decrease with the combination, but p21 accumulated in the cell nucleus. When p21 was silenced, the authors reported a marked decrease (70%) in the percentage of apoptotic cells after the combination. The authors concluded that this apoptosis is mediated by p21 independently of p53, and suggested clinical testing in tumors expressing p21. They noted that the mismatch between p21 gene and protein levels needs further investigation.

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) experiments on human mesothelioma cell lines, including drug treatment, genome-wide gene expression (microarray) analysis, protein analysis and p21 gene silencing
• Who was studied: Four human mesothelioma cell lines: MSTO-211H (main experiments), NCI-H2452 (NCI), IST-Mes1 (Mes1) and IST-Mes2 (Mes2). Gene results were also checked in human mesothelioma samples described in the group's earlier work.
• Exposure: Piroxicam (a non-steroidal anti-inflammatory drug) and cisplatin (a chemotherapy drug), each alone and in combination. The drugs were given at the concentration able to reduce cell proliferation by 50%, for 8, 24 and 48 hours. Asbestos exposure was not studied.
• Main results:
  • In MSTO-211H cells, cisplatin alone produced a 14% apoptotic induction.
  • In MSTO-211H cells, piroxicam plus cisplatin produced a 33% apoptosis increase after 24 hours compared with untreated control cells, measured by flow cytometry.
  • No apoptotic induction was detected at 8 hours with either single or combined treatment.
  • A second method (Annexin V staining) showed up to a 37% apoptosis increase with the combination compared with control in MSTO-211H cells.
  • The NCI and Mes1 cell lines showed a similar apoptotic increase after combined treatment. No significant apoptosis was detected in Mes2 cells with single or combined treatment.
  • Microarray analysis of MSTO-211H cells detected 536 differentially expressed probe sets. No differentially expressed genes were found with cisplatin alone.
  • The p21 gene (CDKN1A) was one of the few genes up-regulated in the cell cycle network after combined treatment.
  • Western blot did not detect an increase in total p21 protein, and the authors noticed a decrease with the combined treatment.
  • With the combined treatment, the location of p21 inside the cell changed, and p21 accumulated in the nucleus.
  • After p21 silencing, MSTO-211H cells given the combined treatment showed a marked decrease (70%) in the percentage of apoptotic cells. Apoptosis was unaffected when a control siRNA was used.
• The authors' conclusion: The authors concluded that apoptosis induced by the piroxicam plus cisplatin combination is mediated by p21 in a p53-independent way. In their abstract they suggested the combination might be tested in clinical settings in tumors that express p21.
• Limitations the authors state:
  • The authors noted a discrepancy between p21 gene activity and p21 protein levels in the combined treatment, which they said needs further investigation.

Topics

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

Medical terms in this study, explained in our Lexicon: Apoptosis, Cisplatin, Mesothelioma, Malignant Mesothelioma, Asbestos Exposure, Chemotherapy.

Related studies

• Efficacy of piroxicam plus cisplatin-loaded PLGA nanoparticles in inducing apoptosis in mesothelioma cells — C. Menale, M.T. Piccolo, et al. (2015)
• Mechanisms of cisplatin-induced cell death in malignant mesothelioma cells: role of inhibitor of apoptosis proteins (IAPs) and caspases — I.L. Cregan, A.M. Dharmarajan, et al. (2013)
• Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin — L.L. Belyanskaya, T.M. Marti, et al. (2007)
• Synergistic effect of non-transmissible Sendai virus vector encoding the c-myc suppressor FUSE-binding protein-interacting repressor plus cisplatin in the treatment of malignant pleural mesothelioma — A. Kitamura, K. Matsushita, et al. (2011)
• Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma — S. Wang, L. Jiang, et al. (2016)
• Combined hyaluronate-based films loaded with pemetrexed and cisplatin for the treatment of malignant pleural mesothelioma: Preliminary evaluation in an orthotopic tumor recurrence model — F. Sonvico, S. Barbieri, et al. (2018)

Browse more research in PloS One, or return to medical research.