Zebularine exerts its antiproliferative activity through S phase delay and cell death in human malignant mesothelioma cells

Our plain-English summary of Zebularine exerts its antiproliferative activity through S phase delay and cell death in human malignant mesothelioma cells, by Y. Takemura, M. Satoh, K. Hatanaka, et al (Bioscience, Biotechnology, and Biochemistry, 2018).

The study

• Authors: Y. Takemura, M. Satoh, K. Hatanaka, S. Kubota
• Journal: Bioscience, Biotechnology, and Biochemistry
• Published: 2018;82(7):1159-1164
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma is an asbestos-related aggressive tumor and current therapy remains ineffective. Zebularine as a DNA methyltransferase (DNMT) inhibitor has an anti-tumor effect in several human cancer cells. The aim of the present study was to investigate whether zebularine could induce antiproliferative effect in human malignant mesothelioma cells. Zebularine induced cell growth inhibition in a dose-dependent manner. In addition, zebularine dose-dependently decreased expression of DNMT1 in all malignant mesothelioma cells tested. Cell cycle analysis indicated that zebularine induced S phase delay. Zebularine also induced cell death in malignant mesothelioma cells. In contrast, zebularine did not induce cell growth inhibition and cell death in human normal fibroblast cells. These results suggest that zebularine has a potential for the treatment of malignant mesothelioma by inhibiting cell growth and inducing cell death.

In plain English

This was a laboratory study of cells grown in dishes. It did not study people or asbestos exposure. The authors tested zebularine, a drug that blocks DNA methyltransferase (DNMT) enzymes, on three human malignant mesothelioma cell lines and one normal human fibroblast line. In the growth and cell-damage tests, cells were treated for 48 hours at 10 to 200 μM (micromolar). Zebularine reduced growth of all three mesothelioma lines, and the effect grew with the dose. The concentration that cut survival by half was 39.6 μM for ACC-MESO, 40.6 μM for EHMES-1 and 95.2 μM for Y-MESO. It also caused cell death and lowered DNMT1 protein levels. In the normal fibroblasts, these tests showed no slowing of growth and no cell damage. In ACC-MESO cells given 100 μM, the share in the S phase of the cell cycle rose from 8.77% untreated to 16.76% at 24 hours and 25.98% at 48 hours. Proteins linked to programmed cell death also changed. The authors concluded that zebularine induced antiproliferative effects in these cells and that further research is needed on clinical use.

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) experiment on human cell lines grown in culture
• Who was studied: Three human malignant mesothelioma cell lines (ACC-MESO 1, Y-MESO 8A, EHMES-1) and one human normal fibroblast cell line (SF-TY), obtained from the JCRB Cell Bank, Osaka, Japan
• Exposure: The drug zebularine, a DNA methyltransferase (DNMT) inhibitor. The growth and cytotoxicity tests used 10 μM to 200 μM for 48 hours. The cell cycle tests used 100 μM for 24 hours (ACC-MESO and EHMES-1) and 48 hours (ACC-MESO). The apoptosis protein tests used 100 μM. Asbestos was not part of the experiments.
• Main results:
  • Zebularine inhibited growth of all three mesothelioma cell lines in a dose-dependent manner. The concentration that decreased survival by 50% was 39.6 μM for ACC-MESO.
  • The 50% survival-reducing concentration was 40.6 μM for EHMES-1 cells and 95.2 μM for Y-MESO cells.
  • In the LDH assay, zebularine caused dose-dependent cytotoxic (cell-damaging) effects in all three mesothelioma cell lines.
  • The authors reported that zebularine caused cell death, as well as growth arrest, in the malignant mesothelioma cells.
  • Zebularine at 10, 50 and 100 μM lowered DNMT1 protein levels in all three mesothelioma cell lines, and the reduction was greater at higher doses.
  • In the normal fibroblast line (SF-TY), treated at 10 to 200 μM for 48 hours, zebularine did not induce growth inhibition or cytotoxicity in these tests.
  • In ACC-MESO cells treated with 100 μM zebularine, the percentage of cells in S phase was 8.77% in untreated controls, 16.76% at 24 hours and 25.98% at 48 hours. The authors interpreted this as S phase delay.
  • In ACC-MESO and EHMES-1 cells, zebularine increased Bax and decreased pro-caspase-3, which the authors read as caspase-3 activation. A sub-G1 cell population was not detected.
  • Zebularine increased p53 protein in Y-MESO cells and increased serine-15 phosphorylation of p53 in EHMES-1 and Y-MESO cells. p53 protein was not detected in ACC-MESO cells.
• The authors' conclusion: The authors concluded that zebularine induced antiproliferative effects in malignant mesothelioma cells, and that further research is needed to explore its potential for clinical use in malignant mesothelioma.
• Limitations the authors state:
  • The authors state that the precise mechanism by which zebularine causes S phase delay is not yet known.
  • The authors state that further research is needed before zebularine's potential for clinical use can be judged.

Topics

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

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

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