The levels of HDAC1 and thioredoxin1 are related to the death of mesothelioma cells by suberoylanilide hydroxamic acid

Our plain-English summary of The levels of HDAC1 and thioredoxin1 are related to the death of mesothelioma cells by suberoylanilide hydroxamic acid, by B.R. You, W.H. Park (International Journal of Oncology, 2016).

The study

• Authors: B.R. You, W.H. Park
• Journal: International Journal of Oncology
• Published: 2016;48(5):2197-204
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Mesothelioma is an aggressive tumor which is mainly derived from the pleura of lung. In the present study, we evaluated the anticancer effect of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor on human mesothelioma cells in relation to the levels of HDAC1, reactive oxygen species (ROS) and thioredoxin (Trx). While 1 µM SAHA inhibited cell growth in Phi and ROB cells at 24 h, it did not affect the growth in ADA and Mill cells. Notably, the level of HDAC1 was relatively overexpressed among Phi, REN and ROB cells. SAHA induced necrosis and apoptosis, which was accompanied by the cleavages of PARP and caspase-3 in Phi cells. This agent also increased the loss of mitochondrial membrane potential (MMP, ΔΨm) in Phi cells. All the tested caspase inhibitors attenuated apoptosis in SAHA-treated Phi cells whereas HDAC1 siRNA enhanced the apoptotic cell death. SAHA increased intracellular ROS levels including O2•- in Phi cells. N-acetyl cysteine (NAC) and vitamin C (Vit.C) significantly reduced the growth inhibition and death of Phi cells caused by SAHA. This drug decreased the mRNA and protein levels of Trx1 in Phi and ROB cells. Furthermore, Trx1 siRNA increased cell death and O2•- level in SAHA-treated Phi cells. In conclusion, SAHA selectively inhibited the growth of Phi and ROB mesothelioma cells, which showed the higher basal level of HDAC1. SAHA-induced Phi cell death was related to oxidative stress and Trx1 levels.

In plain English

This laboratory study used cultured cells, not patients. The authors tested SAHA, a drug that blocks histone deacetylase enzymes (HDACs), on human mesothelioma cell lines; two normal mesothelial lines were included to compare baseline HDAC1 levels. Asbestos was not tested. At 5 µM for 24 hours, SAHA reduced growth of the Phi and ROB lines by about 30-40% versus untreated cells. ADA and Mill cells were not significantly affected. Sensitive lines had higher baseline HDAC1; resistant lines, lower. In Phi cells, SAHA caused apoptosis (programmed cell death) and raised reactive oxygen species. It also increased a necrosis marker, but necrosis inhibitors did not significantly reduce cell death; the authors judged necrosis only partly involved. SAHA lowered the antioxidant protein thioredoxin1 (Trx1) in Phi and ROB cells. In Phi cells, the antioxidants N-acetyl cysteine and vitamin C reduced SAHA's growth inhibition and cell death, while silencing HDAC1 or Trx1 increased them. Without SAHA, HDAC1 silencing alone induced cell death in Phi cells, and Trx1 silencing induced apoptosis. The authors concluded SAHA-induced Phi cell death was related to oxidative stress and Trx1 levels.

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) study of human cell lines grown in culture, with results reported as the mean of at least three independent experiments
• Who was studied: Seven human mesothelioma cell lines (ADA, CON, Hmeso, Mill, Phi, REN, ROB) and two normal human mesothelial cell lines (HM69, HM72), all from the University of Hawaii Cancer Center. The article reports SAHA's effects in mesothelioma cells. The normal lines appear in the comparison of baseline HDAC1 levels. There were no human subjects.
• Exposure: The drug SAHA (an HDAC inhibitor), mainly at 5 µM for 24 hours. In some experiments it was combined with caspase inhibitors, with the antioxidants N-acetyl cysteine (NAC) and vitamin C, or with siRNA silencing of HDAC1 or Trx1. Asbestos exposure was not studied; it is mentioned only in the introduction.
• Main results:
  • In Phi and ROB mesothelioma cells, 5 µM SAHA reduced growth by about 30-40% compared with untreated control cells
  • In ADA and Mill mesothelioma cells, 5 µM SAHA did not significantly affect growth at 24 hours
  • Baseline HDAC1 levels were higher in the SAHA-sensitive Phi, REN and ROB cells and lower in the SAHA-resistant ADA and Mill cells
  • The two normal mesothelial cell lines differed from each other in baseline HDAC1 levels
  • In Phi cells, SAHA increased annexin V-positive (apoptotic) cells and caused cleavage of PARP and caspase-3
  • SAHA increased LDH release, a marker of necrosis, in Phi cells. However, the necrosis inhibitors NecroX-2 and necrostatin1 did not significantly reduce cell death (data not shown), and the authors described necrosis as only partly related to Phi cell death.
  • In SAHA-treated Phi cells, silencing HDAC1 with siRNA significantly increased growth inhibition. HDAC1 siRNA alone also induced cell death in Phi cells not treated with SAHA.
  • In Phi cells, 5 µM SAHA significantly increased reactive oxygen species levels
  • In SAHA-treated Phi cells, the antioxidants NAC and vitamin C blocked growth inhibition and LDH release, and significantly reduced annexin V-positive cells
  • In Phi and ROB cells, 5 µM SAHA decreased Trx1 mRNA and protein levels. In Phi cells, Trx1 siRNA increased growth inhibition both with and without SAHA.
  • The authors reported that Trx1 siRNA made Phi cells more sensitive to SAHA and on its own induced apoptosis in Phi cells not treated with SAHA
• The authors' conclusion: The authors concluded that SAHA inhibited the growth of Phi and ROB cells among the mesothelioma cells tested, that these cells had relatively higher HDAC levels, and that SAHA-induced Phi cell death was related to oxidative stress and Trx1 levels

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, Pleura, Reactive Oxygen Species (ROS), Necrosis, Apoptosis, Oxidative Stress.

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• Histone deacetylase inhibitors in malignant pleural mesothelioma: preclinical rationale and clinical trials — P.K. Paik, L.M. Krug (2010)
• Upregulation of 9 genes, including that for thioredoxin, during epithelial differentiation of mesothelioma cells — X. Sun, K. Dobra, et al. (2000)
• Diarachidonoylphosphoethanolamine induces apoptosis of malignant pleural mesothelioma cells through a Trx/ASK1/p38 MAPK pathway — A. Tsuchiya, Y. Kaku, et al. (2015)
• High dose of ascorbic acid induces cell death in mesothelioma cells — Y. Takemura, M. Satoh, et al. (2010)

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