Resveratrol contributes to chemosensitivity of malignant mesothelioma cells with activation of p53

Our plain-English summary of Resveratrol contributes to chemosensitivity of malignant mesothelioma cells with activation of p53, by Y.J. Lee, I.S. Park, Y.J. Lee, et al (Food and Chemical Toxicology, 2014).

The study

• Authors: Y.J. Lee, I.S. Park, Y.J. Lee, J.H. Shim, M.K. Cho, H.S. Nam, J.W. Park, M.H. Oh, S.H. Lee
• Journal: Food and Chemical Toxicology
• Published: 2014;63:153-60
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Resveratrol is a naturally occurring polyphenolic phytoalexin with chemopreventive properties. We previously reported a synergistic anti-proliferative effect of resveratrol and clofarabine against malignant mesothelioma (MM) cells. Here, we further investigated molecular mechanisms involved in the synergistic interaction of these compounds in MM MSTO-211H cells. Resveratrol, in combination with clofarabine, time-dependently induced a strong cytotoxic effect with the nuclear accumulation of phospho-p53 (p-p53) in MSTO-211H cells, but not in normal mesothelial MeT-5A cells. Combination treatment up-regulated the levels of p-p53, cleaved caspase-3, and cleaved PARP proteins. Gene silencing with p53-targeting siRNA attenuated the sensitivity of cells to the combined treatment of two compounds. Analyses of p53 DNA binding assay, p53 reporter gene assay, and RTP-CR toward p53-regulated genes, including Bax, PUMA, Noxa and p21, demonstrated that induced p-p53 is transcriptionally active. These results were further confirmed by the siRNA-mediated knockdown of p53 gene. Combination treatment significantly caused the accumulation of cells at G1 phase with the increases in the sub-G0/G1 peak, DNA ladder, nuclear fragmentation, and caspase-3/7 activity. Taken together, these results demonstrate that resveratrol and clofarabine synergistically elicit apoptotic signal via a p53-dependent pathway, and provide a scientific rationale for clinical evaluation of resveratrol as a promising chemopotentiator in MM.

Copyright © 2013 Elsevier Ltd. All rights reserved.

In plain English

This was a laboratory study of cells grown in dishes. It did not study patients and did not examine asbestos exposure. The authors, in Korea, tested the plant compound resveratrol with the chemotherapy drug clofarabine. They used one human mesothelioma cell line, MSTO-211H, and one normal human mesothelial cell line, MeT-5A. With 15 micromolar resveratrol plus 40 nanomolar clofarabine, the mesothelioma cells were nearly all killed within 5 days. At 5 days, cell viability was about 78.6% of untreated cells with resveratrol alone and 68.5% with clofarabine alone. The normal cells showed only a mild slowing of growth. The combination raised an activated form of the p53 protein in the mesothelioma cells and increased p53-controlled genes, including Bax, p21 and PUMA. Blocking p53 reduced the cell killing, though not completely. Markers of programmed cell death rose: caspase-3/7 activity was 203.8% of untreated levels with the combination, against 121% and 134.8% for each compound alone. The authors concluded that the cell death depended on caspases, with p53 acting upstream, and that studies in animals are still needed.

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 mesothelioma cell line MSTO-211H and the normal mesothelial cell line MeT-5A. No people or animals were studied.
• Exposure: Resveratrol (15 micromolar) and the chemotherapy drug clofarabine (40 nanomolar), alone or in combination. Some experiments used a range of doses. No asbestos exposure was studied.
• Main results:
  • In MSTO-211H mesothelioma cells, the combination nearly wiped out the cells within 5 days. At 5 days, MTT-measured viability relative to untreated control cells was approximately 78.6% with resveratrol alone and 68.5% with clofarabine alone.
  • In normal mesothelial MeT-5A cells, the same treatments caused only a mild slowing of growth.
  • The combination strongly increased phospho-p53, cleaved caspase-3 and cleaved PARP in MSTO-211H cells. This was not seen in MeT-5A cells.
  • In MSTO-211H cells, silencing p53 prevented the cell killing caused by the combination.
  • In MSTO-211H cells, the combination increased gene activity of p53 and its targets Bax, p21 and PUMA.
  • In MSTO-211H cells given the combination, the fraction of cells in the sub-G0/G1 group (a sign of dying cells) was 11.6% after 24 hours and 18.4% after 48 hours.
  • Share of MSTO-211H cells in the G1 phase: 76.37% at 24 hours and 83.45% at 48 hours with the combination, against 78.14% and 75.01% in untreated cells.
  • With the combination, approximately 23% of attached MSTO-211H cells showed shrunken and fragmented nuclei.
  • In MSTO-211H cells, caspase-3/7 activity relative to untreated cells was 203.8% with the combination, 121% with resveratrol alone and 134.8% with clofarabine alone.
• The authors' conclusion: The authors concluded that cell death caused by resveratrol plus clofarabine depended on caspases, with increased activity of normal (wild-type) p53 acting upstream.
• Limitations the authors state:
  • Knocking down p53 did not completely prevent the cell killing. The authors took this to mean that other factors besides p53 also contribute.
  • The work was done only in cultured cells. The authors state that further studies are needed to test the two compounds in living animals.

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, MeT-5A Cells.

Related studies

• Resveratrol and clofarabine induces a preferential apoptosis-activating effect on malignant mesothelioma cells by Mcl-1 down-regulation and caspase-3 activation — Y.J. Lee, Y.J. Lee, et al. (2015)
• 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)
• 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 inhibition of mesothelioma cell growth by the combination of clofarabine and resveratrol involves Nrf2 downregulation — Y.J. Lee, J.H. Im, et al. (2012)
• 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)
• Cisplatin and resveratrol induce apoptosis and autophagy following oxidative stress in malignant mesothelioma cells — Y.J. Lee, G.J. Lee, et al. (2016)

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