Premature senescence induced by DNA demethylating agent (Decitabine) as therapeutic option for malignant pleural mesothelioma

Our plain-English summary of Premature senescence induced by DNA demethylating agent (Decitabine) as therapeutic option for malignant pleural mesothelioma, by S. Amatori, I. Bagaloni, D. Viti, et al (Lung Cancer, 2011).

The study

• Authors: S. Amatori, I. Bagaloni, D. Viti, M. Fanelli
• Journal: Lung Cancer
• Published: 2011;71(1):113-5
• Type of article: Letter
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The drug-dependent induction of premature senescence in neoplastic cells is considered per se an important tumor suppressive mechanism. DNA demethylating agents recently introduced in clinical trials, such as 5-aza-cytidine (Decitabine) and its derivatives, have been extensively characterized in recent years as antiproliferative compounds that act through multiple mechanisms, which have not yet been fully clarified. We recently analyzed the introduction of Decitabine in therapy for malignant pleural mesothelioma (MPM) observing that, despite the ability to induce profound biological effects in MPM cells, the drug failed to generate a massive apoptotic response. Since one of the most intriguing aspects of DNA demethylating agents is the possibility to accelerate the senescent response of tumor cells, we investigated the hypothesis of Decitabine inducing, in vitro, the premature aging of MPM cells.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

In plain English

This laboratory report, published as a letter to the editor, tested in cell cultures whether the drug decitabine, a DNA demethylating agent, induces premature senescence in malignant pleural mesothelioma cells. Senescence is a permanent halt in cell growth. The study did not examine asbestos exposure or patients. The authors treated two primary mesothelioma cell lines (MES-PR 99 and MES-SS 01) and one immortalized line (H28) with different decitabine doses for 6 days. Treated cells looked enlarged and flattened, like senescent cells. The share of cells positive for a galactosidase senescence marker rose with dose. In H28 cells, the genes p21 and GADD45A rose strongly, p27, ATM and ATR rose modestly, and the growth marker MKI67 showed a significant drop. A marker of DNA damage response rose strongly after 24 and 48 hours. Senescence-associated heterochromatic foci were not detected. The authors concluded that the findings strongly suggest DNA demethylating strategies can induce a senescent-like state in these cells, and called this a plausible therapeutic option to study further. They said it was difficult to tell whether DNA damage or demethylation plays the major role.

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) cell-culture experiment, reported as a letter to the editor
• Who was studied: Malignant pleural mesothelioma cell lines: two primary lines (MES-PR 99 and MES-SS 01) and one immortalized line (H28); no human participants
• Exposure: The DNA demethylating drug decitabine (DAC) at different doses for 6 days. The dose range is printed as 0.1 to 10 with the unit symbol damaged in the text. Asbestos exposure was not studied.
• Main results:
  • Decitabine-treated mesothelioma cells showed the shape features of senescent cells, such as an enlarged and flattened appearance.
  • The fraction of cells positive for the galactosidase senescence marker increased with decitabine dose (and with time, data not shown), in both H28 cells and the primary cells.
  • In H28 cells treated with decitabine at a final concentration of 1 (unit damaged in text), p21 and GADD45A were strongly up-regulated, and p27, ATM and ATR mRNA levels increased modestly.
  • In the same H28 gene expression analysis, the proliferation marker MKI67 was significantly down-regulated.
  • Phosphorylated histone H2AX, a marker of DNA damage response, strongly increased after 24 (not shown) and 48 hours of decitabine at doses of 1 and 10, in both H28 and primary cells.
  • Senescence-associated heterochromatic foci (SAHF) were not detected after 2 or 6 days of decitabine treatment.
• The authors' conclusion: The authors concluded that the findings strongly suggest DNA demethylating strategies can induce a senescent-like phenotype in malignant pleural mesothelioma cells. They described this as a plausible therapeutic option to investigate further.
• Limitations the authors state:
  • The authors stated that, at this stage of knowledge, it was difficult to determine whether the DNA-damage response or DNA demethylation plays the major role in the cells' response to decitabine.

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, Clinical Trial.

Related studies

• Decitabine, differently from DNMT1 silencing, exerts its antiproliferative activity through p21 upregulation in malignant pleural mesothelioma (MPM) cells — S. Amatori, F. Papalini, et al. (2009)
• Immunomodulatory activity of SGI-110, a 5-aza-2'-deoxycytidine-containing demethylating dinucleotide — S. Coral, G. Parisi, et al. (2013)
• Progressive aberrant methylation of the RASSF1A gene in simian virus 40 infected human mesothelial cells — S. Toyooka, M. Carbone, et al. (2002)
• Methylation profile landscape in mesothelioma: possible implications in early detection, disease progression, and therapeutic options — X. Zhang, N. Tang, et al. (2015)
• Gemcitabine reactivates epigenetically silenced genes and functions as a DNA methyltransferase inhibitor — S.G. Gray, A.M. Baird, et al. (2012)
• Hypomethylation reduced the aggressive potential of human malignant mesothelioma cells — N.Y. Kim, M.C. Kim, et al. (2016)

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