cancer development. The topical application of caffeine to human
skin provides protection from UV light via DNA repair
mechanisms.27 Caffeine has been shown to prevent or reverse
UV damage by inhibiting the ataxia-telangiectasia and Rad3-
related protein (ATR)-checkpoint kinase 1 (Chk1) pathway28
involved in cell cycle control.29 By inhibiting the ATR-Chk1
pathway, caffeine prevents tumor growth and promotes
apoptosis. Lastly, should UV-damage occur, topical caffeine
can eliminate UV-damaged keratinocytes30 and subsequently
inhibit skin cancer development. While this discussion
frequently uses UV light as the inducer of ROS, it has been
shown that both visible light and infrared also induce ROS.31
Our product provides a “second line” of defense in that its components
also directly inhibit various inflammatory pathways.
The cyclooxygenase (COX)-2 and lipoxygenase (LOX) pathways
catalyze the production of pro-inflammatory substances, including
prostaglandins and leukotrienes.32,33 Various biochemical
pathways are also associated with the induction of inflammatory
cytokines (tumor necrosis factor-α, IL-6, and IL-1β) that stimulate
the growth of tumor cells.34 Resveratrol works to diminish inflammation
by stopping COX-2 activity,35 likely by inhibition of the
protein kinase C (PKC) signal transduction suppressing COX-2
expression.36 This finding is important because PKC is up regulated
in some types of cancer.37,38,39 Green tea phenols (GTPs) have
also been shown to have an effect on the COX pathway. GTPs in
drinking water reduced inflammation markers COX-2, prostaglandin
E2, proliferating cell nuclear antigen, and cyclin D1 in mice
with skin damage that developed after exposure to UV radiation.40
Other studies showed that GTPs: (1) inhibit ornithine decarboxylase,
COX, and LOX; and (2) inhibit release of interleukins 1, 8,
10, and 12,41 which are all pro-inflammatory molecules. The third
compound in our product, caffeine, takes yet another approach
in countering inflammation. Topical caffeine inhibits cyclic AMP
phosphodiesterase, which results in increased levels of cAMP in
skin, which, in turn, reduces inflammatory reactions.42,43
Lastly, it is important to consider that an increase in cutaneous
blood supply would carve a convenient pathway for inflammatory
markers to reach the skin. Angiogenesis is defined as
the production of new blood vessels and/or altered permeability
of existing blood vessels. A key element that stimulates
angiogenesis is vascular endothelial growth factor (VEGF).
Resveratrol, GTPs, and caffeine down regulate angiogenesis.
A study by Pietrasik and colleagues44 demonstrated that resveratrol
modulates normal somatic cells, leading to a decrease
of the angiogenic activity of endothelial cells. Mesothelial cells
treated with resveratrol created an angiogenesis-suppressive
milieu, reflected by the inhibited proliferation and migration of
endothelial cells. This suppressive effect continued even after
the cells were removed from resveratrol exposure. Endothelial
cells treated directly with resveratrol also showed anti-angiogenic
activity. The anti-angiogenic effect of resveratrol may be associated with its activation of glycogen-synthase kinase
3b (GSK3b), which results in decreased production of VEGF
via down-regulation of b-catenin.45 GTPs play an anti-angiogenic
role by inhibiting phosphorylation of VEGF receptors46
required for VEGF binding. Meanwhile, pretreatment of cells
with caffeine significantly reduces adenosine-induced VEGF
promoter activity and VEGF and IL-8 expression.47 The antiangiogenic
effects of all three compounds in our product may
directly reduce redness.
The skin product’s unique combination of resveratrol, green
tea polyphenols, and caffeine reduces facial redness in most
patients after 3 to 6 weeks of continuous treatment and may
provide further improvement with additional treatment.
The study was initiated and funded by one of the authors
(N.I.B.). That author contributed to the conceptualization and
design of the product but holds no patents and does not benefit
from its sale. This product is commercialized as Replenix Power
of Three by Topix Pharmaceuticals.
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Berson, D. Natural antioxidants. J Drugs Dermatol 2008;7(7 Suppl):S7-S12.
Farris, P. Idebenone, green tea, and coffeeberry extract: new and innovative antioxidants. Dermatol Ther. 2007 Sep-Oct;20(5):322-9.
Palmer DM, Kitchin JS. Oxidative damage, skin aging, antioxidants and a novel antioxidant rating system. J Drugs Dermatol. 2010 Jan;9(1):11-5.
Bradu SM, Jagdeo J, Bajor E, Shwereb C, Hannan R, Brody N. Inhibition of hydrogen peroxide-generated lipid peroxidation product 4-hydroxy-2-nonenal by green tea polyphenols in human fibroblast WS-1 cells. Society for Investigative Dermatology 65th Annual Meeting, Providence, RI. 2004 Abstract. Poster.
Jagdeo J, Bradu SM, Sorace M, Bajor E, Ellis L, Sieminska J, Brody NI. Inhibition of hydrogen peroxide- generated intracellular free radicals by caffeine and green tea polyphenols alone and in combination in human fibroblast WS-1 cells quantified by dihydrorhodamine. Anti-Aging World Conference, 2005. Abstract.
Silverberg JI, Jagdeo J, Patel M, Siemenska J, Michl J, Brody N. Green Tea Extract Protects Human Skin Fibroblasts From reactive Oxygen Species-Associated Cell Death. Accepted Journal of Drugs in Dermatology 2011.
Baxter RA. Anti-aging properties of resveratrol: review and report of a potent new antioxidant skin care formulation. J Cosmet Dermatol. 2008 Mar;7(1):2-7.
Jagdeo J, Adams L, Lev-Tov H, Sieminska J, Michl J, Brody N. Anti-Oxidant Function of Resveratrol Demonstrated via Modulation of Reactive Oxygen Species in Normal Human Skin Fibroblasts in Vitro. Journal of Drugs and Dermatology. December 2010.
Elmets CA, Singh D, Tubesing K, Matsui M, Katiyar S, Mukhtar H. Cutaneous photoprotection from ultraviolet injury by green tea polyphenols. J Am Acad Dermatol. 2001 Mar;44(3):425-32.
Heffernan TP, Kawasumi M, Blasina A, Anderes K, Conney AH, Nghiem P. ATR-Chk1 pathway inhibition promotes apoptosis after UV treatment in primary human keratinocytes: potential basis for the UV protective effects of caffeine. J Invest Dermatol. 2009 Jul;129(7):1805-15. Epub 2009 Feb 26.
Pinnell SR. Cutaneous photodamage, oxidative stress, and topical antioxidant protection. J Am Acad Dermatol. 2003 Jan;48(1):1-19; quiz 20-2.
Kalish R, Brody N. The effects of tumor facilitating factor of B16 melanoma on the macrophage. J Invest Dermatol. 1983 Mar;80(3):162-7.
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