Cosmeceutical Critique: ResveratrolDr. Leslie Baumann
Volume 37, Issue 6, Page 24 (June 2006)
Resveratrol (3,4',5-trihydroxystilbene) is a polyphenolic phytoalexin compound present in the skin and seeds of grapes, berries, peanuts, and other foods. The preponderance of data on resveratrol is very recent, with increased research activity following a seminal report in the journal Science in 1997 (Science 1997;275:218–20; Biochem. Biophys. Res. Commun. 2005;331:993–1000; Cancer Res. 2001;61:1604–10).
In the 1997 study, purified resveratrol was found to exhibit major inhibitory activity against cancer initiation, promotion, and progression. Specifically, its antioxidant and antimutagenic potency and induction of phase II drug-metabolizing enzymes were seen as counter to carcinogenic initiation. Resveratrol hindered cyclooxygenase and hydroperoxidase and initiated anti-inflammatory effects, thereby demonstrating antipromotion activity. The induction of human promyelocytic leukemia cell differentiation by this newly discovered botanical ingredient also thwarted the progress of carcinogenic activity. In addition, resveratrol demonstrated significant inhibitory effects in vitro with carcinogen-induced preneoplastic lesions in mouse mammary glands, and in vivo with tumorigenesis in the two-stage mouse skin cancer model (Science 1997;275:218–20).
Since then, copious research has been performed on this compound, which has developed a strong reputation as a potent antioxidant, anti-inflammatory, and antiproliferative agent (Toxicol. Appl. Pharmacol. 2003;186:28–37; Biochem. Pharmacol. 2002;63:99–104; Biomed. Papers 2003;147:137–45). Most importantly, it is considered to act as a chemopreventive agent against skin cancer and to exert an antiproliferative influence on oral-squamous, breast, colon, and prostate cancer cells, in which it triggers apoptosis (Pancreas 2002;25:e71–6; J. Biol. Chem. 2003;278:41482–90). Research has confirmed its inhibitory effects on tumor initiation, promotion, and progression (Biomed. Papers 2003;147:137–45; Front. Biosci. 2002;7:784–92; Skin Pharmacol. Appl. Skin Physiol. 2002;15:297–306).
The most recent data indicate that resveratrol protects against UVB-mediated cutaneous damage in SKH-1 hairless mice, particularly by inhibiting survivin, the overexpression of which is associated with various cancers (Photochem. Photobiol. 2005;81:25–31; FASEB J. 2005;19:1193–5).
In just a few years, resveratrol has become one of the most promising cancer-preventive agents (Mol. Carcinog. 2002;33:244–50; Cancer Res. 2001;61:1604–10).
In early studies of this potent polyphenol, pretreatment of mouse skin significantly lowered oxidative stress induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) and restored glutathione levels and superoxide dismutase activity (Drugs Exp. Clin. Res. 1999;25:65–77). Resveratrol pretreatment also showed dose-dependent, broad-spectrum reversal or reduction of several TPA-induced carcinogenic effects by disrupting the pathways of reactive oxidants, researchers have suggested (Cancer Lett. 1998;134:81–9). TPA-mediated increases in the expression of cyclooxygenases (COX-1, COX-2), c-myc, c-fos, c-jun, TGF-ß1, and TNF-a were all inhibited by resveratrol pretreatment (Cancer Lett. 1998;134:81–9; Skin Pharmacol. Appl. Skin Physiol. 2001;14:373–85).
In other studies, resveratrol treatment of human epidermoid carcinoma A432 cells inhibited growth and caused G1 phase arrest of the cell cycle, apoptosis, dose- and time-dependent induction of p21WAF1, and decreases in expression of various proteins (Clin. Cancer Res. 2001;7:1466–73; Skin Pharmacol. Appl. Skin Physiol. 2001;14:373–85).
In an early study, grape seed proanthocyanidin extract (GSPE) containing resveratrol at 5,000 ppm was found to facilitate oxidant-induced vascular endothelial growth factor (VEGF) expression in cultured keratinocytes, with pretreatment of HaCaT keratinocytes upregulating hydrogen peroxide and TNF-a-induced VEGF expression and release. The authors concluded that resveratrol-containing GSPE has the potential to ameliorate dermal wounds and other skin conditions (Free Radic. Biol. Med. 2001;31:38–42).
The same investigators subsequently used topical GSPE to successfully treat dermal wounds in vivo. They found that the extract increased the rate of wound contraction and closure as well as the expression of VEGF and tenascin in wound edge tissue. Greater cell density and definition in the hyperproliferative epithelial region, along with augmented deposition of connective tissue, were also observed (Free Radic. Biol. Med. 2002;33:1089–96). Many of the same investigators also reported that a combination of grape seed extract and resveratrol promoted VEGF expression, noting that such activity is important in wound angiogenesis (Ann. N.Y. Acad. Sci. 2002;957:239–49).
Among its numerous antioxidant activities, resveratrol potently inhibits nitric oxide generation and inducible nitric oxide synthase protein expression (Ann. N.Y. Acad. Sci. 2002;957:210–29).
A potential application of resveratrol may have been hinted at 3 years ago by researchers who demonstrated that pretreatment suppressed NF-?ß activation in cultured rat PC12 cells transiently induced by ß-amyloid. Resveratrol also thwarted other effects of the ß-amyloid peptide, which is believed to account for the plaques that are characteristic of brain tissue in patients with Alzheimer's disease. The polyphenol was found to attenuate cytotoxicity, apoptosis, and intracellular reactive oxygen intermediate formation (Free Radic. Biol. Med. 2003;34:1100–10).
Photoprotection and Tumor Inhibition
In a recent study of resveratrol's effects on UVB-mediated skin tumorigenesis, SKH-1 hairless mice were exposed to UVB twice weekly for 28 weeks. Resveratrol was topically applied to the test group 30 minutes before or 5 minutes after each UVB exposure. Pre- and posttreatment applications were found to equally lower tumor incidence and to postpone tumorigenesis onset compared with controls. The authors concluded that their findings are the first results with direct implications for human skin cancers, speculating that resveratrol is suitable for inclusion in emollients, patches, sunscreens, and other products intended to prevent skin cancer and other conditions associated with exposure to the sun (FASEB J. 2005;19:1193–5, Epub 2005 Apr 18).
The molecular mechanisms of resveratrol's antitumorigenic properties were hinted at in a study of its effects on TPA-induced COX-2 expression in mouse skin. Researchers observed dose-dependent inhibition of COX-2 expression after pretreatment of the dorsal skin of female ICR mice. They also found decreases in the phosphorylation of extracellular signal-regulated protein kinase (ERK) and in the catalytic activity of ERK and p38 mitogen-activated protein kinase, as well as diminished DNA binding of activator protein-1 induced by TPA (Biofactors 2004;21:33–9).
Recent reports by the same team confirm resveratrol's photoprotective activity. The topical application of resveratrol to SKH-1 hairless mice significantly inhibited UVB-induced skin edema (Front. Biosci. 2002;7:784–92). In another experiment with SKH-1 hairless mice, topical resveratrol significantly inhibited UVB-mediated increases in bifold skin thickness and edema, and greatly diminished UVB-induced lipid peroxidation, COX, and ornithine decarboxylase (ODC) activity, as well as protein expression of the ODC enzyme (Toxicol. Appl. Pharmacol. 2003;186:28–37). The authors concluded that topically applied resveratrol appears to impart significant photoprotective capacity against the damage wrought by UVB radiation.
Additional research by this team showed that resveratrol inhibits UVB-mediated activation of NF-?ß in a dose- and time-dependent manner in normal human epidermal keratinocytes, and that this pathway plays an important role in the botanical's photoprotective activity (Neoplasia 2003;5:74–82). In an experiment by some of the same investigators, resveratrol was topically applied to SKH-1 hairless mice 30 minutes before exposure to UVB. Critical cell cycle regulatory proteins—the target of the investigation—were substantially downregulated as a result of the treatment. The researchers concluded that this potent antioxidant could play an important role in preventing UVB-mediated photodamage and carcinogenesis (Oncogene 2004;23:5151–60).
Resveratrol has also been evaluated as an antifungal or antimicrobial because it is synthesized in response to injury or fungal attack (Free Radic. Res. 2002;36:621–31; FEMS Yeast Res. 2003;4:79–85).
In one study, researchers assessed the activity of resveratrol against bacteria and dermatophytes known to be important causes of human skin infections, including Staphylococcus aureus, Enterococcus faecalis, and Pseudomonas aeruginosa. The compound inhibited the growth of the bacteria and of the fungal species Trichophyton mentagrophytes, Trichophyton tonsurans, Trichophyton rubrum, Epidermophyton floccosum, and Microsporum gypseum. The investigators concluded that the potential dermatologic applications of resveratrol and its analogs appear to be even wider than previously believed, and may include treatment of diabetic wounds (Biochem. Pharmacol. 2002;63:99–104).
In another study with direct implications for new dermatologic applications, investigators evaluated the in vivo effects of resveratrol on herpes simplex virus (HSV), building on prior success in vitro. The topical application of two concentrations of resveratrol cream (12.5% and 25%) to the abraded epidermis of SKH-1 mice infected with HSV-1 suppressed lesion development when applied multiple times a day within 1 or 6 hours after infection, but not 12 hours after infection. In a comparison between resveratrol cream, 10% docosanol cream (Abreva), and 5% acyclovir ointment (Zovirax), resveratrol cream and acyclovir were comparably effective, whereas mice treated with docosanol developed lesions at the same rate as cream-only controls. The resveratrol cream successfully inhibited lesion formation when the experiment was repeated with an HSV-1 acyclovir-resistant virus (Antiviral Res. 2004;61:19–26).
At the Store
Resveratrol is an ingredient in Caudalíe's Lifting Serum with grapevine resveratrol ($78/oz.) and Eye Lifting Serum with grapevine resveratrol ($68/oz.). It is also a key ingredient in three Cellex-C International Inc. products: Advanced-C Serum ($115/oz.), Advanced-C Neck Firming Cream ($115/2 oz.), and Advanced-C Skin Tightening Cream ($135/2 oz.).
I discussed the benefits of grape seed extract in a previous column (SKIN &; ALLERGY NEWS, November 2003, p. 26). It appears, though, that not only grape skin and seeds, but also berries, peanuts, and other foods are sources of resveratrol. For those of you who drink red wine, the knowledge that you may be helping your skin might increase your enjoyment.
© 2006 Elsevier Inc. All rights reserved.