Synergistic inhibition of mesothelioma cell growth by the combination of clofarabine and resveratrol involves Nrf2 downregulation

Our plain-English summary of Synergistic inhibition of mesothelioma cell growth by the combination of clofarabine and resveratrol involves Nrf2 downregulation, by Y.J. Lee, J.H. Im, D.M. Lee, et al (BMB Reports, 2012).

The study

• Authors: Y.J. Lee, J.H. Im, D.M. Lee, J.S. Park, S.Y. Won, M.K. Cho, H.S. Nam, Y.J. Lee, S.H. Lee
• Journal: BMB Reports
• Published: 2012;45(11):647-52
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

We previously reported that MSTO-211H cells have a higher capacity to regulate Nrf2 activation in response to changes in the cellular redox environment. To further characterize its biological significance, the response of Nrf2, a transcription factor that regulates ARE-containing genes, on the synergistic cytotoxic effect of clofarabine and resveratrol was investigated in mesothelioma cells. The combination treatment showed a marked growth-inhibitory effect, which was accompanied by suppression of Nrf2 activation and decreased expression of heme oxygenase-1 (HO-1). While transient overexpression of Nrf2 conferred protection against the cytotoxicity caused by their combination, knockdown of Nrf2 expression using siRNA enhanced their cytotoxic effect. Pretreatment with Ly294002, a PI3K inhibitor, augmented the decrease in HO-1 level by their combination, whereas no obvious changes were observed in Nrf2 levels. Altogether, these results suggest that the synergistic cytotoxic effect of clofarabine and resveratrol was mediated, at least in part, through suppression of Nrf2 signaling.

In plain English

This was a laboratory study of a human mesothelioma cell line called MSTO-211H, grown in culture. It did not study patients or asbestos exposure. The authors tested whether the cancer drug clofarabine (40 nM) combined with resveratrol (15 μM), a plant-derived compound, slowed cell growth more than expected, and whether a protein called Nrf2 was involved. After 48 hours, the combination inhibited cell growth by 50.01%, compared with 26.8% expected if the two effects simply added together. The combination reduced Nrf2 in the cell nucleus and lowered HO-1, a protein whose level the authors used to measure Nrf2 activity. Cells made to produce extra Nrf2 survived the combination significantly better. Under the combination, cells with Nrf2 reduced had about 65% viability, compared with 78% in comparison cells given a control siRNA and the same combination. Adding an antioxidant, NAC, raised viability at 72 hours from about 54.1% to 67.7% of control cells. The authors concluded that the combined effect was mediated, at least in part, by suppressing Nrf2 and PI3K/Akt signaling. They said more studies are needed to explain how it works.

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 a human mesothelioma cell line
• Who was studied: human mesothelioma cell line MSTO-211H, obtained from the American Type Culture Collection; no patients were studied
• Exposure: no asbestos exposure was studied; cells were treated with the drug clofarabine (40 nM) and resveratrol (15 μM), alone or combined; sulforaphane was also tested, as were the inhibitors Ly294002 and PD98059 and the antioxidant NAC
• Main results:
  • Resveratrol alone reduced MSTO-211H cell viability more strongly than sulforaphane alone
  • After 48 h, clofarabine (40 nM) plus resveratrol (15 μM) produced 50.01% growth inhibition, compared with an additive effect of the two agents of 26.8%
  • Clofarabine combined with sulforaphane was neither synergistic nor additive (data not shown)
  • The clofarabine plus resveratrol combination strongly reduced Nrf2 in the cell nucleus, and this was accompanied by a decrease in HO-1
  • Cells made to overexpress Nrf2 had significantly higher viability under the combination treatment than cells given the empty vector
  • Under the combination treatment, cells with Nrf2 knocked down by siRNA had viability of approximately 65%, compared with 78% in cells given control siRNA and the same combination
  • The combination inhibited Akt phosphorylation. Pretreatment with the PI3K inhibitor Ly294002 increased the drop in HO-1 but caused no obvious change in Nrf2
  • Pretreatment with the antioxidant NAC raised viability at 72 h under the combination from approximately 54.1% to 67.7% of control cells
• The authors' conclusion: The authors concluded that the synergy of clofarabine and resveratrol was mediated, at least in part, through suppression of Nrf2 and PI3K/Akt signaling. They said their data suggest the potential importance of targeting Nrf2 in mesothelioma
• Limitations the authors state:
  • The authors stated that additional studies are needed to explain the mechanism of the synergy
  • The authors stated it is unclear how much Nrf2-driven HO-1 expression accounts for drug resistance

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.

Related studies

• 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)
• 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)
• Reactive oxygen species and PI3K/Akt signaling play key roles in the induction of Nrf2-driven heme oxygenase-1 expression in sulforaphane-treated human mesothelioma MSTO-211H cells — Y.J. Lee, H.Y. Jeong, et al. (2012)
• Resveratrol contributes to chemosensitivity of malignant mesothelioma cells with activation of p53 — Y.J. Lee, I.S. Park, et al. (2014)
• 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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