Resveratrol and clofarabine induces a preferential apoptosis-activating effect on malignant mesothelioma cells by Mcl-1 down-regulation and caspase-3 activation

Our plain-English summary of Resveratrol and clofarabine induces a preferential apoptosis-activating effect on malignant mesothelioma cells by Mcl-1 down-regulation and caspase-3 activation, by Y.J. Lee, Y.J. Lee, S.H. Lee (BMB Reports, 2015).

The study

• Authors: Y.J. Lee, Y.J. Lee, S.H. Lee
• Journal: BMB Reports
• Published: 2015;48(3):166-71
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

We previously demonstrated that resveratrol and clofarabine elicited a marked cytotoxicity on malignant mesothelioma (MM) MSTO-211H cells but not on the corresponding normal mesothelial MeT-5A cells. Little is known of the possible molecules that could be used to predict preferential chemosensitivity on MSTO-211H cells. Resveratrol and clofarabine induced down-regulation of Mcl-1 protein level in MSTO-211H cells. Treatment of cells with cycloheximide in the presence of proteasome inhibitor MG132 suggested that Mcl-1 protein levels were regulated at the post-translational step. The siRNA-based knockdown of Mcl-1 in MSTO-211H cells triggered more growth-inhibiting and apoptosis-inducing effects with the resultant cleavages of procaspase-3 and its substrate PARP, increased caspase-3/7 activity, and increased percentage of apoptotic propensities. However, the majority of the observed changes were not shown in MeT-5A cells. Collectively, these studies indicate that the preferential activation of caspase cascade in malignant cells might have important applications as a therapeutic target for MM.

In plain English

This was a laboratory study of cells grown in dishes. It did not study people or asbestos exposure. The authors, at Soonchunhyang University in Korea, compared a human malignant mesothelioma cell line (MSTO-211H) with a normal human mesothelial cell line (MeT-5A). They treated both with resveratrol, a plant compound, combined with the cancer drug clofarabine. The combination lowered the level of Mcl-1, a protein that helps cells avoid programmed cell death (apoptosis), in the mesothelioma cells, but raised it in the normal cells. This change did not appear at the gene-message level. The authors linked it to protein breakdown. The calculated half-life of Mcl-1 was about 16.7 minutes in the normal cells and 68.1 minutes in the mesothelioma cells. Reducing Mcl-1 with a gene-silencing tool (siRNA) slowed growth more and activated caspase-3, an enzyme that carries out apoptosis, in the mesothelioma cells. The normal cells showed little such activation. The authors concluded that the combination strongly induced apoptosis of mesothelioma cells through caspase-3/7 activity and, at least in part, through lowering Mcl-1. Apart from the half-lives and timing, the text gives no numbers for the size of most of these changes.

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
• Who was studied: Two human cell lines: the malignant mesothelioma cell line MSTO-211H and the normal mesothelial cell line MeT-5A. The work was done at Soonchunhyang University, Cheonan, Korea.
• Exposure: No asbestos exposure was studied. Cells were treated with resveratrol combined with clofarabine (40 nM). The resveratrol dose is printed as '15 M' because a unit symbol was lost. In some cells Mcl-1 was reduced (knocked down) with siRNA (10 nM), and some were given the caspase inhibitor Z-VAD or the proteasome inhibitor MG132.
• Main results:
  • After the combination treatment, Mcl-1 protein fell in MSTO-211H mesothelioma cells and rose in MeT-5A normal cells. Mcl-1 level was inversely related to sensitivity to the treatment. Bcl-xL levels did not change significantly.
  • Mcl-1 messenger RNA did not change detectably in either cell line. The proteasome inhibitor MG132 increased Mcl-1 protein, and the authors took this to mean that Mcl-1 was regulated after the protein was made.
  • The calculated half-life of Mcl-1 protein was about 16.7 min in MeT-5A cells and 68.1 min in MSTO-211H cells.
  • Reducing Mcl-1 with siRNA, combined with the drug treatment, markedly reduced growth of MSTO-211H cells. MeT-5A cells were relatively resistant.
  • Reducing Mcl-1 with siRNA strongly induced cleavage of procaspase-3 and PARP in MSTO-211H cells, a sign of apoptosis. No cleaved procaspase-3 was detected in MeT-5A cells.
  • Reducing Mcl-1 with siRNA raised caspase-3/7 activity in MSTO-211H cells, and the drug combination increased it further. MeT-5A cells showed only small changes. The text gives no numerical values for these changes.
• The authors' conclusion: The authors concluded that combined resveratrol and clofarabine strongly induced apoptosis of mesothelioma cells by enhancing caspase-3/7 activity and, at least in part, by lowering Mcl-1. They suggested that preferential activation of the caspase cascade might offer an alternative approach for treating malignant mesothelioma.
• Limitations the authors state:
  • The authors did not examine the specific mechanisms of the caspase-independent cell death seen in the normal MeT-5A cells.

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, Malignant Mesothelioma, MeT-5A Cells.

Related studies

• Knockdown of Bcl-xL enhances growth-inhibiting and apoptosis-inducing effects of resveratrol and clofarabine in malignant mesothelioma H-2452 cells — Y.J. Lee, I.S. Hwang, et al. (2014)
• Synergistic anti-cancer effects of resveratrol and chemotherapeutic agent clofarabine against human malignant mesothelioma MSTO-211H cells — Y.J. Lee, Y.J. Lee, et al. (2013)
• Resveratrol contributes to chemosensitivity of malignant mesothelioma cells with activation of p53 — Y.J. Lee, I.S. Park, et al. (2014)
• Synergistic inhibition of mesothelioma cell growth by the combination of clofarabine and resveratrol involves Nrf2 downregulation — Y.J. Lee, J.H. Im, et al. (2012)
• Cisplatin and resveratrol induce apoptosis and autophagy following oxidative stress in malignant mesothelioma cells — Y.J. Lee, G.J. Lee, et al. (2016)
• The flavonoid resveratrol suppresses growth of human malignant pleural mesothelioma cells through direct inhibition of specificity protein 1 — K.A. Lee, Y.J. Lee, et al. (2012)

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