Update on resveratrol

• Found abundantly in nature, this polyphenolic phytoalexin is believed to exhibit a wide range of biologic activity.

• Potent antioxidant, anti-inflammatory, and antiproliferative properties.

• Highly studied polyphenolic substance also considered a chemopreventive agent against skin cancer.

• In small studies, has contributed to antiaging, antiacne, antierythema, and skin-lightening results.

Resveratrol (trans-3,5,4’-trihydroxystilbene), a polyphenolic phytoalexin synthesized in nearly 70 plant species, is found to be particularly abundant in Vitis vinifera (grape vine) and its derivatives (e.g., red wine, purple grape juice), various berries, peanuts, jackfruit, pomegranate, eucalyptus, the roots of Polygonum cuspidatum (Japanese knotweed, which is used in traditional Chinese and Japanese medicine to treat dermatitis, among other conditions)¹, Scots pine, spruce, corn lily, gnetum, and butterfly orchid.^2-6 Several studies have demonstrated that resveratrol possesses potent antioxidant, anticarcinogenic, anti-inflammatory, as well as antimicrobial characteristics.^7-11 Specifically, in vitro and in vivo studies have shown that resveratrol exerts chemopreventive and antiproliferative activity against various cancers, including skin cancer, by suppressing cellular events associated with tumor initiation, promotion, and progression, and triggering apoptosis in such tumor cells.^12-14 It also is reputed to impart antiaging benefits.¹⁵ This column will focus on recent research findings pertaining to effects on the skin as well as topical uses of this botanical agent, the main source of which, V. vinifera , has been used since antiquity.

Resveratrol was first identified from the roots of Veratrum grandiflorum (white hellebore) in 1940,^16-19 but research on the compound did not take root until after a 1997 report in Science suggested chemopreventive properties. In that study, purified resveratrol was found to exhibit major inhibitory activity against cancer initiation, promotion, and progression.²⁰ Since then, copious research on this botanical compound has yielded a reputation as a strong antioxidant, anti-inflammatory, and antiproliferative agent.^7,21,22 Most importantly, resveratrol is considered to act as a chemopreventive agent against skin cancer and antiproliferative influence on oral squamous, breast, colon, and prostate cancer cells.^12,14 It is also one of the most studied polyphenolic compounds.

Skin cancer and photoprotection

In 2012, Osmond et al. conducted in vitro and in vivo experiments to assess the potential of resveratrol as a chemotherapy adjunct for melanoma treatment. Resveratrol significantly reduced melanoma cell viability in both melanoma cell lines tested, and selectively spared cells in the nonmalignant fibroblast lines, compared with its cytotoxic impact on melanoma cells. Further, cytotoxicity to malignant cells was greatly enhanced by 72 hours of treatment with resveratrol and temozolomide, compared with temozolomide treatment alone. No significant differences were seen in vivo. The researchers concluded that the in vitro antitumor activity of resveratrol suggested its potential as a therapeutic agent in melanoma management.²³

Resveratrol has been shown to protect against UVB-mediated cutaneous damage in SKH-1 hairless mice. Afaq et al. demonstrated that UVB-induced skin edema was significantly suppressed by the topical application of resveratrol to SKH-1 hairless mice.⁷

In a different study by the same team, topically applied resveratrol significantly inhibited UVB-mediated increases in bifold skin thickness and edema and greatly diminished UVB-induced lipid peroxidation, cyclo-oxygenase and ornithine decarboxylase (ODC) activities, as well as protein expression of the ODC enzyme in SKH-1 hairless mice.²⁴ In an experiment by some of the same researchers, resveratrol was topically applied to SKH-1 hairless mice 30 minutes before exposure to UVB; 24 hours later, significant decreases were observed in bifold skin thickness, hyperplasia, and leukocyte infiltration. Critical cell cycle regulatory proteins, the target of the investigation, were substantially down-regulated because of the resveratrol. The investigators concluded that resveratrol might have the potential to play a significant role in preventing UVB-mediated photodamage and carcinogenesis.²⁵

More recently, in 2015, Sirerol et al. found that the topical treatment with pterostilbene, a natural dimethoxy analog of resveratrol, effectively shielded SKH-1 hairless mice from UVB-induced photodamage and carcinogenesis.²⁶

Interestingly, recent in vitro studies by Sticozzi and colleagues have shown that topical resveratrol dose-dependently protected human keratinocytes from cigarette smoke–induced reduction of scavenger receptor B1 protein expression²⁷ and can lower cigarette smoke–induced reactive oxygen species and carbonyl formation in human keratinocytes.²⁸

Antiaging activity

In 2010, Giardina et al. performed an in vitro study to evaluate the tonic-trophic characteristics of resveratrol alone and resveratrol plus N-acetyl-cysteine on cultured skin fibroblasts. Both formulations dose-dependently increased cell proliferation and inhibition of collagenase activity.²⁹

In 2012, Wu et al. investigated the protective effects of resveratrate, a stable derivative of resveratrol, against damage to human skin caused by repetitive solar simulator UV radiation (ssUVR) in 15 healthy human volunteers. Six sites on nonexposed dorsal skin of each participant were assessed, with four sites exposed to ssUVR and the remaining sites serving as positive control (ssUVR only) and baseline control (no treatment or exposure). The researchers noted minimal erythema on areas treated with resveratrate and the resveratrol derivative significantly inhibited sunburn cell formation. They concluded that resveratrate protects the skin against sunburn and suntan caused by repetitive ssUVR.⁴

Also that year, Buonocore et al. conducted a placebo-controlled, double-blind study in 50 subjects that revealed the antiaging efficacy of a dietary nutraceutical blend of resveratrol and procyanidin. Specifically, skin moisturization and elasticity improved while wrinkle depth and skin roughness lessened after 60 days of treatment.³⁰

In a 2013 in vitro study of the skin permeation kinetics of polyphenols using diffusion cells via ex vivo pig skin and a cellulose membrane, Zillich et al. showed that several polyphenols, including resveratrol, epigallocatechin gallate, quercetin, rutin, and protocatechuic acid formulated in oil-in-water emulsions could permeate the stratum corneum and were identified in the epidermis and dermis. The team concluded that their findings validate the use of polyphenols as active ingredients in antiaging products.³¹

In 2014, Farris et al. found that the topical application of resveratrol in a proprietary blend (1% resveratrol, 0.5% baicalin, 1% vitamin E) yielded a statistically significant amelioration of fine lines and wrinkles, hyperpigmentation, radiance, as well as skin roughness, firmness, elasticity, and laxity in a small study over 12 weeks.³²

Skin lightening

Resveratrol has also been used as a promising topical treatment for hyperpigmentation disorders.33 The compound has been shown to work synergistically with 4-n-butylresorcinol (a derivative of resorcinol, one of the main phenols found in argan oil) to reduce tyrosinase levels and significantly diminish melanin synthesis, more effectively than either compound alone.34 In 2012, Franco et al. observed that resveratrol can inhibit tyrosinase but it does not sufficiently suppress melanin production to justify its use as a lone skin-whitening agent in pharmaceutical formulations, but warrants attention as a coadjuvant for treating hyperpigmentation.35 The skin-lightening capacity of resveratrol supported by a 2013 study in which 52 medicinal plants grown in Korea were tested for human tyrosinase activity and the dried stems of the grape tree V. vinifera were found to potently suppress human tyrosinase, and more effectively than arbutin.36 It is worth noting that resveratrol, through its antioxidant activity and possible inhibitory effect on cytochrome P450 2E1 expression, has been shown to protect mouse primary hepatocytes from hydroquinone-induced cytotoxicity.37 Also, J.M. Galgut and S.A. Ali, noted the gathering of pigment cells and resultant skin lightening from the effects of topical ethanolic extract of Arachis hypogaea (peanuts, which contain half the resveratrol of red wine) on the tail melanophores of tadpole Bufo melanostictus, concluding that resveratrol merits attention for potential clinical use as a nontoxic melanolytic agent to treat hyperpigmentation.38,34

Acne

Resveratrol is considered an emerging agent in the topical armamentarium for treating acne.39 In a single-blind pilot study in 2011, Fabbrocini et al. investigated the potential therapeutic impact of resveratrol on 20 patients with acne. A resveratrol-containing hydrogel was applied daily on the right side of the face for 60 days, with the left side receiving the hydrogel vehicle as control. No adverse effects were reported and all patients were satisfied with the treatment. Researchers reported a 53.75 % mean reduction in the Global Acne Grading System score on the resveratrol-treated sides and a 6.10 % decrease on the control sides. Histologic analysis revealed a statistically significant reduction of lesions in areas treated with resveratrol (66.7 % mean reduction in the average area of microcomedones on the resveratrol-treated sides vs. 9.7% reduction on the control sides).40

A 2015 comprehensive literature review of randomized clinical trials and controlled trials by Dall’oglio et al. found that cosmetics with antimicrobial and anti-inflammatory ingredients, including resveratrol, may accelerate acne resolution.41

Significantly, resveratrol is one of the novel acne treatments considered to have little potential for susceptibility to antibiotic resistance to Propionibacterium acnes.42

Erythema

In a small 2013 study by Ferzli et al., 16 subjects with erythema applied a formulation containing resveratrol, green tea polyphenols, and caffeine twice daily to the whole face. Clinical photographs and spectrally enhanced images taken before treatment and every 2 weeks through 3 months were assessed. The investigators reported that improvement was seen in 16 of 16 clinical images and 13 of 16 spectrally enhanced images. Erythema reduction was observable by 6 weeks of treatment, and no adverse effects were observed.43

Conclusion

Resveratrol is emerging as a compound with the potential to deliver significant health benefits, particularly in terms of photoprotective, cancer preventive, and cardioprotective activity. While there are 2 strong decades of research, more is necessary to elucidate the full potential of resveratrol as a first-line dermatologic therapy. Preclinical data do support the use of resveratrol in various product types (e.g., emollients, patches, sunscreens, and additional skin care products) intended to prevent skin cancer or to prevent or treat other conditions caused or exacerbated by solar exposure, such as photoaging. I look forward to seeing clinical evidence of the efficacy of topically applied resveratrol.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever. She also developed and owns the Baumann Skin Type Solution skin-typing systems and related products.

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