New histone deacetylase inhibitors improve cisplatin antitumor properties against thoracic cancer cells

Our plain-English summary of New histone deacetylase inhibitors improve cisplatin antitumor properties against thoracic cancer cells, by F. Gueugnon, P.F. Cartron, C. Charrier, et al (Oncotarget, 2014).

The study

• Authors: F. Gueugnon, P.F. Cartron, C. Charrier, P. Bertrand, J.F. Fonteneau, M. Gregoire, C. Blanquart
• Journal: Oncotarget
• Published: 2014;5(12):4504-15
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Histone deacetylase inhibitors (HDACi) have shown promising antitumor effects on numerous cancer cells including malignant pleural mesothelioma (MPM) and lung adenocarcinoma (ADCA) cells. However, clinical trials using these compounds alone have shown limited efficacy against solid tumors. Therefore, new molecules are being developed and combinations with classical chemotherapeutic drugs are being tested. Here, we have evaluated on three MPM and three lung ADCA cell lines the antitumor potential of four new HDACi compounds, either alone or in combination with cisplatin. These effects were compared with those of vorinostat, an HDACi approved for cancer treatments. First, we characterized the HDAC mRNA expression profiles of tumor cells and showed an increase of the classI/classII HDAC ratio. We then treated cancer cells with these new HDACi and observed a cell-death induction and an increase of HDACi target genes and proteins expression. This was particularly evident for NODH compound (pan-HDACi) which had similar effects at nanomolar concentrations as micromolar concentrations of vorinostat. Interestingly, we observed that the HDACi/cisplatin combination strongly increased cell-death and limited resistance-phenotype emergence as compared with results obtained when the drugs were used alone. These results could be exploited to develop MPM and lung ADCA treatments combining chemotherapeutic approaches.

In plain English

This laboratory study used cells grown in dishes; it did not study people or asbestos exposure. The authors tested four new experimental histone deacetylase inhibitor drugs (ODB, NODB, ODH and NODH) on three malignant pleural mesothelioma (MPM) and three lung adenocarcinoma cell lines, comparing them with the existing drug vorinostat (SAHA). NODH worked at nanomolar doses; the others needed micromolar doses. The authors then combined SAHA, NODB or NODH with the chemotherapy drug cisplatin, at doses chosen to kill about 30% of cells alone. These combinations killed more than 70% of lung adenocarcinoma cells and more than 80% of MPM cells. Over eleven days of repeated treatment, they prevented 'less-sensitive' cells from emerging and/or controlled growth better in all tested cell lines. On normal mesothelial cells, SAHA-cisplatin and NODH-cisplatin caused no extra toxicity beyond cisplatin alone, but NODB-cisplatin did. The authors concluded that cisplatin combined with these drugs could be of real interest for treating these cancers, and stated that NODH's properties still need confirming in living organisms.

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 and normal mesothelial cells
• Who was studied: Three malignant pleural mesothelioma cell lines (Meso13, Meso56, Meso34) and three lung adenocarcinoma cell lines (ADCA153, ADCA72, A549). Five of these were established from patients' pleural fluids; A549 came from the American Type Culture Collection. Normal pleural mesothelial cells and commercial peritoneal mesothelial cells (MESF-1) served as controls. The enzyme-ratio analysis was extended to 18 MPM cell lines and 2 isolations of pleural mesothelial cells.
• Exposure: No asbestos exposure was studied. In the apoptosis, cell-cycle and gene tests, cells were treated with SAHA, ODB, NODB, ODH or NODH, each at five times its IC50. In the combination tests, cells received SAHA (500 nM), NODB (500 nM) or NODH (5 nM), with or without cisplatin (0.8 mg/l); ODB and ODH were not used in these tests.
• Main results:
  • The ratio of class I to class II HDAC enzyme expression was higher in all cancer cell lines except Meso13 than in normal pleural mesothelial cells.
  • All six cancer cell lines were more sensitive to NODH, which was active in the nanomolar range, than to ODB, NODB, ODH or SAHA, which were active in the micromolar range.
  • Averaged across the six cell lines, 24 hours of treatment at five times the IC50 produced 35% apoptotic cells and 10% necrotic cells. After 48 hours, the necrotic proportion reached 35%.
  • The drugs increased mRNA expression of p21, Semaphorin 3F, E-cadherin and Bim. VEGF expression fell in the lung adenocarcinoma lines but tended to rise in the MPM lines.
  • In the combination tests, SAHA, NODB or NODH were combined with cisplatin, at doses chosen to cause about 30% cell death when each drug was used alone. The combinations caused more than 70% cell death in lung adenocarcinoma cells and more than 80% in MPM cells.
  • With cisplatin alone, the MPM cell lines and A549 showed a 'less sensitive' phenotype from the sixth day.
  • Over eleven days of repeated treatment, the cisplatin combinations (with SAHA, NODB or NODH) prevented the emergence of 'less-sensitive' cells and/or controlled cell growth better in all tested cell lines.
  • On normal MESF-1 mesothelial cells, NODB-cisplatin caused 60% cell death, compared with 30% for cisplatin alone.
  • On normal MESF-1 mesothelial cells, SAHA-cisplatin and NODH-cisplatin caused no extra toxicity beyond cisplatin alone. In MESF-1 cells they caused 40% and 30% cell death, respectively, compared with about 85% in lung adenocarcinoma cells and about 80% in MPM cells.
• The authors' conclusion: The authors concluded that cisplatin combined with these HDAC inhibitors could be of real interest in treating MPM and lung adenocarcinoma. They suggested NODH could be an alternative to existing HDAC inhibitors.
• Limitations the authors state:
  • The authors stated that NODH's improved properties still need to be confirmed in living organisms (in vivo).
  • The authors stated that the protein-level findings from the antibody array need to be confirmed by a larger biochemical study.
  • Because drug activity varied widely between cell lines, the authors could not conclude that any drug acted selectively on MPM versus lung adenocarcinoma cells.
  • The authors' larger MPM mRNA collection did not confirm the apparent high HDAC3 expression seen in the MPM cell lines.

Topics

Medical terms in this study, explained in our Lexicon: Cisplatin, Pleural Mesothelioma, Lung Adenocarcinoma, Clinical Trial.

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