Chemoprevention of skin cancer by grape constituent resveratrol: relevance to human disease?

Abstract

According to the World Cancer Report, skin cancer constitutes approximately 30% of all newly diagnosed cancers in the world, and solar ultraviolet (UV) radiation (particularly, its UVB component; 290-320 nm) is an established cause of approximately 90% of skin cancers. The available options have proven to be inadequate for the management of skin cancers. Therefore, there is an urgent need to develop mechanism-based novel approaches for prevention/therapy of skin cancer. In this study, we evaluated the chemopreventive effects of resveratrol against UVB radiation-mediated skin tumorigenesis in the SKH-1 hairless mouse model. For our studies, we used a UVB initiation-promotion protocol in which the control mice were subjected to chronic UVB exposure (180 mJ/cm2, twice weekly, for 28 weeks). The experimental animals received either a pretreatment (30 min before each UVB) or post-treatment (5 min after UVB) of resveratrol (25 or 50 micro mole/0.2 ml acetone/mouse). The mice were followed for skin tumorigenesis and were killed at 24 h after the last UVB exposure, for further studies. The topical application of skin with resveratrol (both pre- and post- treatment) resulted in a highly significant 1) inhibition in tumor incidence, and 2) delay in the onset of tumorigenesis. Interestingly, the post-treatment of resveratrol was found to impart equal protection than the pretreatment; suggesting that resveratrol-mediated responses may not be sunscreen effects. Because Survivin is a critical regulator of survival/death of cells, and its overexpression has been implicated in several cancers, we evaluated its involvement in chemoprevention of UVB-mediated skin carcinogenesis by resveratrol. Our data demonstrated a significant 1) up-regulation of Survivin (both at protein- and mRNA- levels), 2) up-regulation of phospho-Survivin protein, and 3) down-regulation of proapoptotic Smac/DIABLO protein in skin tumors; whereas treatment with resveratrol resulted in the attenuation of these responses. Our study also suggests that resveratrol enhanced apoptosis in UVB-exposure-mediated skin tumors. Our study, for the first time, demonstrated that 1) resveratrol imparts strong chemopreventive effects against UVB exposure-mediated skin carcinogenesis (relevant to human skin cancers), and 2) the chemopreventive effects of resveratrol may, at least in part, be mediated via modulations in Survivin and other associated events. On the basis of our work, it is conceivable to design resveratrol-containing emollient or patch, as well as sunscreen and skin-care products for prevention of skin cancer and other conditions, which are believed to be caused by UV radiation.

Resveratrol-induced p53-independent apoptosis of human nasopharyngeal carcinoma cells is correlated with the downregulation of ΔNp63

“…28 However, RSV has been shown to induce apoptosis by p53-independent mechanisms in several human cancers. 15,26,27,38 It is important to note that this study shows that RSV's apoptotic effect is independent of p53 even though the level of p53 is upregulated. It is uncertain whether this represents a marker for cell-cycle arrest or cytoprotection.…”

“…12 Trans-resveratrol (RSV), a natural antioxidant and phytoalexin, is widely distributed in grapes, fruits and the root tubers of Polygonum cuspidatum. 14,15 It has been used as an important constituent in Chinese and Japanese folk medicine. There are a growing number of reports showing that RSV can prevent or slow the progression of a wide variety of illnesses, including cancers, 16 cardiovascular disease 17 and ischemia reperfusion injuries 14,18 as well as enhance stress resistance 19 and extend the life spans of various organisms.…”

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

“…[28][29][30] Interestingly, some AHR-antagonizing compounds, such as resveratrol, 30 were also identified to protect mice against UVB-induced skin carcinogenesis by enhancing apoptosis. 31 Thus, it is tempting to speculate that AHR antagonism may counteract tumor initiation by increasing epidermal cell death. Indeed, the AHR is known to modulate apoptosis in many different cell types and tissues in both pro-apoptotic and anti-apoptotic manners.…”

In vitro and in vivo percutaneous absorption of seleno-L-methionine, an antioxidant agent, and other selenium species

“…Reactive oxygen species (ROS) were implicated in the etiology of several skin disorders including skin cancer and photoaging. Skin cancer constitutes about 30% of all newly diagnosed cancers in the world and solar UV radiation, particularly the UVB component, is an established cause of about 90% of skin cancers [2] . In recent years, particular antioxidants have gained considerable attention as means of neutralizing ROS.…”