Resveratrol, but not dihydroresveratrol, induces premature senescence in primary human fibroblasts

Faragher, R. G. A.; Burton, Dominick G. A.; Majecha, Patricia; Fong, Noel S. Y.; Davis, Terence; Sheerin, Angela; Ostler, Elizabeth L.

doi:10.1007/s11357-010-9201-5

Cited by 25 publications

(18 citation statements)

References 32 publications

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“…Data acquired with our dual purpose real-time cell analyzer (RTCA) further highlighted that RSV, RSVT and PTER significantly inhibited the migration of B16F10 cells, while dihydro-RSV, stilbene and RSVN exhibited no similar effect ( Figure 2 E ). The biofunctions of RSV and the analogs have also been studied in other published reports as summarized in Figure 2 F 36 - 46 . As with the published data and our functional experimental testing (Figure 2 F), the RSVN analog shares similar bioactivities with RSV except for the inhibition of cell migration, which indicates that the presence of 4'-hydroxystilbene within the RSV structure is essential for its anti-migration activity.…”

Section: Resultsmentioning

confidence: 99%

Comparative profiling of analog targets: a case study on resveratrol for mouse melanoma metastasis suppression

Chen

Xu³

et al. 2018

Theranostics

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Many plant-specialized metabolites have remedial properties and provide an endless chemical resource for drug discovery. However, most of these metabolites have promiscuous binding targets in mammalian cells and elicit a series of responses that collectively change the physiology of the cells. To explore the potential of these multi-functional and multi-targeted drugs, it is critical to understand the direct relationships between their key chemical features, the corresponding binding targets and the relevant biological effects, which is a prerequisite for future drug modification and optimization.Methods: We introduced and demonstrated a general workflow, called Comparative Profiling of Analog Targets (CPAT), to connect specific biological effects with defined chemical structures of drugs. Using resveratrol (RSV) as an example, we have synthesized and characterized a series of partial functional analogs of RSV. An analog (named RSVN) that specifically lost the inhibitory effect of RSV in cell migration was identified. The binding targets of RSVN and RSV was profiled and compared.Results: Comparative profiling of the RSV and RSVN binding targets showed that, unlike RSV, RSVN failed to target specific components involved in DNA methylation (histone deacetylase 1 [HDAC1] and DNA methyltransferase 3 alpha [DNMT3a]), suggesting that RSV suppresses cell migration through epigenetic regulation. Indeed, RSV treatment recruited HDAC1 and DNMT3a to the promoter region of the focal adhesion kinase (FAK), a key factor involved in cell adhesion, enhanced the promoter methylation, and thus attenuated the protein expression. The inhibitory effect of RSV in cell migration was diminished once FAK expression was restored. Thus, the mechanism of RSV in inhibiting cell migration could be largely accounted to epigenetically control of FAK expression.Conclusion: Our results showed that even though RSV exhibits promiscuous binding, its inhibitory effect on cell migration can be mechanistically understood. First, the presence of 4'-hydroxystilbene within the RSV structure is essential for this activity. Second, it inhibits cell migration through epigenetically based downregulation of FAK expression. Taken together, we propose that CPAT might also be adapted to delineate the specific function of other natural products (NPs) that exhibit binding promiscuity.

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Section: Resultsmentioning

confidence: 99%

Comparative profiling of analog targets: a case study on resveratrol for mouse melanoma metastasis suppression

Chen

Xu³

et al. 2018

Theranostics

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“…Previously Demidenko and Blagosklonny also analysed the effects of resveratrol on human embryonic lung fibroblasts WI-38 and found that resveratrol prevents senescence but this was rather at high, near-toxic concentrations [ 29 ]. On the other hand Faragher et al [ 30 ] showed that above 25μM resveratrol concentrations produces a dose dependent reduction in proliferation of human foetal lung fibroblasts associated with increased SA-β-gal activity. In general, our data are in line with these reports; the only slight difference is that in BJ (foreskin) fibroblasts as low as 10 μM of resveratrol can induce senescence whereas 100μM or over induce apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Induced Premature Senescence Is Associated with DNA Damage Mediated SIRT1 and SIRT2 Down-Regulation

2015

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The natural polyphenolic compound resveratrol (3,4,5-trihydroxy-trans-stilbene) has broad spectrum health beneficial activities including antioxidant, anti-inflammatory, anti-aging, anti-cancer, cardioprotective, and neuroprotective effects. Remarkably, resveratrol also induces apoptosis and cellular senescence in primary and cancer cells. Resveratrol’s anti-aging effects both in vitro and in vivo attributed to activation of a (NAD)-dependent histone deacetylase family member sirtuin-1 (SIRT1) protein. In mammals seven members (SIRT1-7) of sirtuin family have been identified. Among those, SIRT1 is the most extensively studied with perceptive effects on mammalian physiology and suppression of the diseases of aging. Yet no data has specified the role of sirtuins, under conditions where resveratrol treatment induces senescence. Current study was undertaken to investigate the effects of resveratrol in human primary dermal fibroblasts (BJ) and to clarify the role of sirtuin family members in particular SIRT1 and SIRT2 that are known to be involved in cellular stress responses and cell cycle, respectively. Here, we show that resveratrol decreases proliferation of BJ cells in a time and dose dependent manner. In addition the increase in senescence associated β-galactosidase (SA-β-gal) activity and methylated H3K9-me indicate the induction of premature senescence. A significant increase in phosphorylation of γ-H2AX, a surrogate of DNA double strand breaks, as well as in levels of p53, p21CIP1 and p16INK4A is also detected. Interestingly, at concentrations where resveratrol induced premature senescence we show a significant decrease in SIRT1 and SIRT2 levels by Western Blot and quantitative RT-PCR analysis. Conversely inhibition of SIRT1 and SIRT2 via siRNA or sirtinol treatment also induced senescence in BJ fibroblasts associated with increased SA-β-gal activity, γ-H2AX phosphorylation and p53, p21CIP1 and p16INK4A levels. Interestingly DNA damaging agent doxorubicin also induced senescence in BJ fibroblasts associated with decreased SIRT1/2 levels. In conclusion our data reveal that resveratrol induced premature senescence is associated with SIRT1 and SIRT2 down regulation in human dermal fibroblasts. Here we suggest that the concomitant decline in SIRT1/2 expression in response to resveratrol treatment may be a cause for induction of senescence, which is most likely mediated by a regulatory mechanism activated by DNA damage response.

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“…Resveratrol (Sigma Aldrich, UK; 1 ) was used to synthesise dihydroresveratrol 2 as reported previously [ 47 ]. ( E )-N-(4-(3,5-Dimethoxystyryl)phenyl) methanesulfonamide 3 was synthesised from the previously reported nitro-substituted analogue 7 via an Fe/NH 4 Cl reduction to give amine 8 [ 26 ], followed by sulfonylation with methanesulfonyl chloride (Fig.…”

Section: Methodsmentioning

confidence: 99%

Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence

et al. 2017

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BackgroundAltered expression of mRNA splicing factors occurs with ageing in vivo and is thought to be an ageing mechanism. The accumulation of senescent cells also occurs in vivo with advancing age and causes much degenerative age-related pathology. However, the relationship between these two processes is opaque. Accordingly we developed a novel panel of small molecules based on resveratrol, previously suggested to alter mRNA splicing, to determine whether altered splicing factor expression had potential to influence features of replicative senescence.ResultsTreatment with resveralogues was associated with altered splicing factor expression and rescue of multiple features of senescence. This rescue was independent of cell cycle traverse and also independent of SIRT1, SASP modulation or senolysis. Under growth permissive conditions, cells demonstrating restored splicing factor expression also demonstrated increased telomere length, re-entered cell cycle and resumed proliferation. These phenomena were also influenced by ERK antagonists and agonists.ConclusionsThis is the first demonstration that moderation of splicing factor levels is associated with reversal of cellular senescence in human primary fibroblasts. Small molecule modulators of such targets may therefore represent promising novel anti-degenerative therapies.Electronic supplementary materialThe online version of this article (10.1186/s12860-017-0147-7) contains supplementary material, which is available to authorized users.

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Resveratrol, but not dihydroresveratrol, induces premature senescence in primary human fibroblasts

Cited by 25 publications

References 32 publications

Comparative profiling of analog targets: a case study on resveratrol for mouse melanoma metastasis suppression

Comparative profiling of analog targets: a case study on resveratrol for mouse melanoma metastasis suppression

Resveratrol Induced Premature Senescence Is Associated with DNA Damage Mediated SIRT1 and SIRT2 Down-Regulation

Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence

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