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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Resveratrol: a potential chemopreventive agent
  5. Protection of acute UVB exposure-mediated damages by resveratrol
  6. Protection of multiple UVB exposure-mediated damages by resveratrol
  7. Protection of photocarcinogenesis by resveratrol
  8. Protection of UVB exposure-mediated damages in normal human epidermal keratinocytes by resveratrol: involvement of nuclear factor kappa-B pathway
  9. Enhancement of cancer therapeutic effects of ionizing radiation by resveratrol
  10. Conclusions
  11. References

Solar radiation spans a whole range of electromagnetic spectrum including UV radiation, which are potentially harmful to normal cells as well as ionizing radiations which are therapeutically beneficial towards the killing of cancer cells. UV radiation is an established cause of a majority of skin cancers as well as precancerous conditions such as actinic keratosis. However, despite efforts to educate people about the use of sunscreens and protective clothing as preventive strategies, the incidence of skin cancer and other skin-related disorders are on the rise. This has generated an enormous interest towards finding alternative approaches for management of UV-mediated damages. Chemoprevention via nontoxic agents, especially botanical antioxidants, is one such approach that is being considered as a plausible strategy for prevention of photodamages including photocarcinogenesis. In this review, we have discussed the photoprotective effects of resveratrol, an antioxidant found in grapes and red wine, against UVB exposure-mediated damages in vitro and in vivo. In addition, we have also discussed studies showing that resveratrol can act as a sensitizer to enhance the therapeutic effects of ionizing radiation against cancer cells. Based on available literature, we suggest that resveratrol may be useful for (1) prevention of UVB-mediated damages including skin cancer and (2) enhancing the response of radiation therapies against hyperproliferative, precancerous and neoplastic conditions.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Resveratrol: a potential chemopreventive agent
  5. Protection of acute UVB exposure-mediated damages by resveratrol
  6. Protection of multiple UVB exposure-mediated damages by resveratrol
  7. Protection of photocarcinogenesis by resveratrol
  8. Protection of UVB exposure-mediated damages in normal human epidermal keratinocytes by resveratrol: involvement of nuclear factor kappa-B pathway
  9. Enhancement of cancer therapeutic effects of ionizing radiation by resveratrol
  10. Conclusions
  11. References

Solar radiation occurs as a result of nuclear fusion reaction occurring on the sun. Sun light actually contains a broad spectrum of radiation known as the electromagnetic spectrum that includes radio waves, infrared waves, visible light, UV rays, X-rays and gamma-rays (Fig. 1). About half of the solar radiation is in the visible short-wave part of the electromagnetic spectrum, whereas the other half is mostly in the near-infrared part, with some in the UV range of the spectrum (Fig. 1). Solar spectrum also includes X-rays and gamma radiation. The energetic photons from solar radiation (UV, X-rays and gamma-rays) are ionizing, meaning they use atomic interactions to break chemical bonds. This ionizing radiation is known to be hazardous to nearly all tissues or organs of human or animals depending upon the radiation dose and exposure schedule. Due to its prevalence, UV radiation from sun is regarded as the most important and potentially hazardous radiation and environmental toxicant. More than 90% of the total solar radiation that reaches the Earth is UVA radiation (320–400 nm), and the relationship between skin cancer and UVA exposure has been clearly established during recent years (1). UVB radiation (290–320 nm) is the main causative factor for non-melanoma skin cancers (reviewed in 2), with over one million new cases of basal and squamous cell skin cancers diagnosed annually in the United States (3). Further, UV radiation is believed to be a causative factor for several skin cancers and precancerous conditions including actinic keratosis (4). UV radiation also elicits a variety of other adverse effects called the UV response including erythema, hyperplasia, hyperpigmentation, sunburn cells, inflammation, immunosuppression and premature skin aging (5). It is also important to mention here that among all the cancers, skin cancer is believed to be one of the most preventable and/or curable cancer types.

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Figure 1.  Simplified depiction of the electromagnetic spectrum. Both gamma- and X-rays are used for the treatment of cancers while the ultraviolet portion of the electromagnetic spectrum induces cancer formation. Resveratrol has been shown to be effective in enhancing the therapeutic efficacy of ionizing radiation therapies as well as blocking UV-induced damages.

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Primary prevention of UV exposure is currently the most effective means of skin cancer prevention. At present, the two major means of protection from harmful solar radiation are the use of sunscreens and protective clothing. The American Cancer Society and other similar organizations have done considerable efforts in educating the people about these two preventive strategies. Despite these efforts, the incidence of skin cancers and skin-related disorders are on the rise (3). The proper application of a liberal quantity of sunscreen and the specific UV absorption spectrum of the agent used limit the utility of sunscreens while sun protective clothes are often not worn by the population. Thus, the available options are inadequate for the management of UV damages including skin cancers. Therefore, there is a need to develop mechanism-based novel approaches for the prevention and therapy of skin cancer. It is being increasingly appreciated that chemoprevention could be a useful approach in this direction. Chemoprevention, by definition, is a means of cancer control in which the occurrence of the disease can be entirely prevented, slowed or reversed by the administration of one or more naturally occurring and/or synthetic compounds (6–8). In recent years, the naturally occurring compounds, especially the botanical antioxidants, especially those present in the common diet and beverages consumed by human population, have gained considerable attention as chemopreventive agents for potential human benefit (6–10).

Studies have shown that several plant-based antioxidants may be useful in the management of UV-mediated damages. It is known that UV exposure results in an excessive generation of reactive oxygen species (ROS) such as the superoxide anion and hydrogen peroxide (1). ROS can react with DNA, protein and unsaturated fatty acids causing DNA strand breaks, protein–protein DNA crosslinks and oxidative damage (11). ROS have been implicated in adverse effects caused by UV radiation including skin cancers (11). The skin possesses its own “built-in” antioxidant mechanisms to defend itself from ROS damages (12). Excessive exposure to ROS may render the skin’s defense system incapable of coping with its damaging effects. In such scenario, exogenous supplementation of the antioxidants may be a useful strategy for the management of UV exposure-mediated damages including skin cancer. In this review, we will provide information regarding the preventive effects of resveratrol (3,5,4′-trihydroxystilbene), a strong antioxidant amply present in grapes and red wine, against UV radiation-mediated damages. We will also discuss studies showing that resveratrol can act as a potential sensitizer to enhance the antiproliferative effects of ionizing radiation against cancer cells.

Resveratrol: a potential chemopreventive agent

  1. Top of page
  2. Abstract
  3. Introduction
  4. Resveratrol: a potential chemopreventive agent
  5. Protection of acute UVB exposure-mediated damages by resveratrol
  6. Protection of multiple UVB exposure-mediated damages by resveratrol
  7. Protection of photocarcinogenesis by resveratrol
  8. Protection of UVB exposure-mediated damages in normal human epidermal keratinocytes by resveratrol: involvement of nuclear factor kappa-B pathway
  9. Enhancement of cancer therapeutic effects of ionizing radiation by resveratrol
  10. Conclusions
  11. References

In recent years, naturally occurring antioxidant agents have gained considerable attention as chemopreventive agents against cancers (6–10). Studies have shown that dietary antioxidants such as green tea polyphenols, curcumin, silymarin, apigenin and resveratrol afford protection against the development of skin cancer (reviewed in 6–8,13). Further, chemoprevention via nontoxic (often food-based) agents is gaining increasing popularity and attention because it is regarded as safe and is not perceived as “medicine.” An approach to prevent cancer or reduce the risk of cancer development in its early stage is a logical and perhaps the most useful strategy for the management of this disease. Resveratrol, a naturally occurring polyphenolic compound with strong antioxidant properties, is abundantly found in grapes, berries, nuts and red wine (7,14). The cancer chemopreventive property of resveratrol was first reported in 1997, by Jang et al. (14), when the authors demonstrated that resveratrol possesses antimutagenic and anticarcinogenic effects and can effectively block all the three stages of carcinogenesis (initiation, promotion and progression). Following this seminal contribution by Jang et al., many studies evaluated and established the cancer chemopreventive and/or therapeutic potential and other health-beneficial and desirable effects of resveratrol (7,15–20). It is appreciated that an effective and acceptable chemopreventive agent should have little or no toxic effects in normal and healthy cells while having high efficacy against multiple sites with a known mechanism of action. Additionally, the capability of oral consumption, low cost and acceptance by human population are critical factors for widespread use of a chemopreventive agent. Resveratrol possesses most, if not all, of these properties. Following the extensive ongoing research, this agent could be developed as an ideal chemopreventive agent for a variety of diseases including skin cancer and other skin-related disorders.

Protection of acute UVB exposure-mediated damages by resveratrol

  1. Top of page
  2. Abstract
  3. Introduction
  4. Resveratrol: a potential chemopreventive agent
  5. Protection of acute UVB exposure-mediated damages by resveratrol
  6. Protection of multiple UVB exposure-mediated damages by resveratrol
  7. Protection of photocarcinogenesis by resveratrol
  8. Protection of UVB exposure-mediated damages in normal human epidermal keratinocytes by resveratrol: involvement of nuclear factor kappa-B pathway
  9. Enhancement of cancer therapeutic effects of ionizing radiation by resveratrol
  10. Conclusions
  11. References

Short-term (acute) exposure to UV radiation causes damages which are regarded as precursors for the development of skin cancers. In a study by Afaq et al. (21), resveratrol was shown to possess the potential to ameliorate the damages caused by short-term UVB exposure to mouse skin. This study showed that topical application of resveratrol (25 μmol/0.2 mL acetone per mouse) to SKH-1 hairless mice inhibited UVB (180 mJ/cm2) exposure-mediated damage to mouse skin (21). The exposure of mouse skin with UVB radiation significantly increased bifold skin thickness and ear punch weight indicative of edema, whereas pretreatment of skin with resveratrol was found to significantly inhibit the increases in bifold skin thickness and ear punch weight 24 h post-UVB irradiation (21). Further, UVB-irradiation resulted in an induction of infiltration of leukocytes both in the epidermis and dermis at 24 h post-UVB; and pretreatment of the skin with resveratrol was found to result in a marked reduction in the number of infiltrating leukocytes (21). Ornithine decarboxylase (ODC) plays an important role in both normal cellular proliferation as well as the growth and development of tumors (22); therefore, the authors determined the effect of resveratrol on UVB-mediated modulation in ODC activity in SKH-1 hairless mouse skin. Irradiation of mouse skin with UVB significantly increased epidermal ODC activity at 24 h post-treatment, whereas the preapplication of resveratrol (prior to UVB exposure) resulted in a significant inhibition of UVB-caused induction of ODC activity in the epidermis (21). Additionally, the effect of resveratrol on UVB-mediated modulations in the cyclooxygenase (COX) enzyme, which has a critical role in inflammation and cancer development (23), was examined. UVB exposure to the skin significantly increased epidermal COX activity at 24 h following UVB exposure; and the preapplication of resveratrol (prior to UVB irradiation) resulted in a significant inhibition of UVB-mediated increase in epidermal COX activity (21).

Hydrogen peroxide generation is a well-accepted marker of oxidative stress (24) and because resveratrol is a strong antioxidant (25,26), Afaq et al. determined whether resveratrol could inhibit UVB exposure-mediated generation of H2O2 in SKH-1 hairless mouse skin. Interestingly, UVB exposure was found to result in a significant generation of H2O2 in mouse skin, and resveratrol pretreatment resulted in a significant inhibition of H2O2 levels (21). Further, the effects of UVB and/or resveratrol treatments were also assessed on epidermal lipid peroxidation, which is also a well-accepted marker of oxidative stress (27,28). The data demonstrated that UVB exposure significantly induced lipid peroxidation (measured in terms of malondialdehyde production) in the epidermis, and the pretreatment of skin with resveratrol significantly inhibited the UVB-caused increase in epidermal lipid peroxidation (21). This study demonstrated that resveratrol protects against the damages caused by acute UVB exposure, and these protective effects may be mediated via its strong antioxidant properties.

Protection of multiple UVB exposure-mediated damages by resveratrol

  1. Top of page
  2. Abstract
  3. Introduction
  4. Resveratrol: a potential chemopreventive agent
  5. Protection of acute UVB exposure-mediated damages by resveratrol
  6. Protection of multiple UVB exposure-mediated damages by resveratrol
  7. Protection of photocarcinogenesis by resveratrol
  8. Protection of UVB exposure-mediated damages in normal human epidermal keratinocytes by resveratrol: involvement of nuclear factor kappa-B pathway
  9. Enhancement of cancer therapeutic effects of ionizing radiation by resveratrol
  10. Conclusions
  11. References

Multiple exposures of UV radiation to skin causes an increased risk of skin cancer development as well as other precancerous cutaneous disorders including actinic keratoses (29,30). Reagan-Shaw et al. (31) studied the protective effect of resveratrol against multiple UVB exposure-mediated damages to SKH-1 hairless mouse skin. In this model, the SKH-1 hairless mice were subjected to multiple UVB exposures (180 mJ/cm2 × 7 exposures on alternate days) and resveratrol (10 μmol/0.2 mL acetone per mouse) was topically applied to mouse skin prior to each UVB exposure. This model represented human exposure to solar UV radiations on a week long vacation or outside activities under bright sun. In this study, resveratrol was found to reverse UVB-mediated increases in bifold skin thickness and ear punch weight, indicative of cutaneous edema (31). Further, resveratrol also inhibited multiple UVB-mediated (1) hyperplasia and the infiltration of leukocytes into the epidermis and dermis, both of which are regarded as inflammatory indicators and (2) increase in the protein levels of proliferating cell nuclear antigen, a marker of proliferation (31). Furthermore, the authors evaluated the involvement of cdks and cyclins, which are critical molecules for the progression of cell cycle, in photoprotective effects of resveratrol against UVB exposure-mediated damages in SKH-1 hairless mouse skin. Western blot- and immunohistochemical-analyses demonstrated that multiple UVB exposures to mouse skin resulted in significant increases in cdk-2, cdk-4, cdk-6 and cyclin D2 protein levels in epidermis; whereas resveratrol pretreatment significantly reversed these effects (31). In addition, it was found that multiple UVB exposures caused a significant up-regulation in WAF1/p21 and KIP1/p27 protein levels. Interestingly, resveratrol pretreatment was found to result in a further enhancement in UVB exposure-mediated increase in WAF1/p21 (31). As studies have shown that regulation of WAF1/p21 may be dependent on the tumor suppressor p53, in this study, the effects of UVB and/or resveratrol treatments were determined on the modulation in p53 protein. Multiple UVB exposures significantly increased p53 protein levels; and in a fashion similar to the response on WAF1/p21, resveratrol treatment prior to UVB exposures resulted in a further enhancement in p53 protein levels (31). Finally, repeated UVB exposures was also found to cause an increase in the protein levels of mitogen-activated protein kinase (MAPK) 1/2 along with MAPK kinase-1; whereas topical application of resveratrol prior to UVB exposures significantly reversed the UVB-mediated responses in these proteins (31). Taken together, this study suggested that the antiproliferative effects of resveratrol might be mediated via modulations in the cki-cyclin-cdk network and the MAPK-pathway (31). Based on the outcome of this study, the authors suggested that resveratrol might be useful for prevention of UVB-mediated damages including skin cancer.

In a follow-up study from this group, using the same protocol, the authors conducted experiments to determine the involvement of inhibitor of apoptosis protein family (IAP) survivin during resveratrol-mediated protection from multiple UVB exposures in the SKH-1 hairless mouse skin (32). This study by Aziz et al. (32) demonstrated that multiple UVB irradiations significantly up-regulated Ki-67 protein levels in skin and a pretreatment of the skin with resveratrol resulted in a marked reduction in UVB exposure-mediated up-regulation of Ki-67. As Ki-67 is known to be expressed in the cells at all proliferative stages of the cell cycle (33,34), this data demonstrated the antiproliferative potential of resveratrol against the hyperproliferative response of UVB. Further, this study demonstrated a significant induction of COX-2 and ODC by multiple UV treatments and pretreatment of skin with resveratrol significantly down-regulated the UVB-mediated increase in COX-2 and ODC levels (32). Further, the authors demonstrated that multiple UVB exposures significantly increased the survivin protein and mRNA levels in mouse skins whereas the prior topical application of resveratrol to mouse skin resulted in a significant down-modulation of UVB-mediated increases in this pro-survival molecule (32). This is an important finding because survivin has been shown to be overexpressed in human cancers of prostate, lungs, breast, colon, brain, liver and pancreas (35–37). Furthermore, the authors demonstrated that multiple UVB exposures to SKH-1 hairless mouse skin resulted in a significant increase in phosphorylation of survivin at Thr34 and pretreatment with resveratrol reversed this response of UV exposure (32). The Smac/DIABLO protein is released from mitochondria and binds to and neutralizes the inhibitory activity of IAPs during apoptosis (38). Aziz et al. (32) also demonstrated that concurrent with UVB-caused up-regulation of survivin, an appreciable down-modulation of Smac/DIABLO protein mouse skin was observed, and the pretreatment with resveratrol resulted in restoration of this UV-mediated effect.

The survivin pathway is intimately involved with the process of apoptosis, therefore Aziz et al. assessed whether UVB-mediated modulations in this critical pathway were associated with apoptosis in mouse skin. The effects of UVB and/or resveratrol treatments were assessed with the M30 CytoDEATH protein, a unique protein for determination of early apoptosis (39). Multiple UVB exposures were shown to induce apoptosis in mouse skin, whereas pretreatment of the skin with resveratrol resulted in a further enhancement of M30 immunostaining indicating an enhanced apoptosis response (32). This suggests that resveratrol protects against UVB-mediated damages to mouse skin by apoptotic elimination of damaged cells via an inhibition of the survivin pathway (Fig. 2). Based on these findings, the authors suggested that resveratrol may be useful for the prevention of UVB-mediated cutaneous damages including skin cancer.

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Figure 2.  Molecular mechanism of chemoprevention of UVB-mediated damages by resveratrol. The molecules which are inhibited by resveratrol during UVB-mediated damage are shown in blue, whereas those shown to be up-regulated by resveratrol are depicted in green. Gray lines indicate a possible mechanism of action.

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Protection of photocarcinogenesis by resveratrol

  1. Top of page
  2. Abstract
  3. Introduction
  4. Resveratrol: a potential chemopreventive agent
  5. Protection of acute UVB exposure-mediated damages by resveratrol
  6. Protection of multiple UVB exposure-mediated damages by resveratrol
  7. Protection of photocarcinogenesis by resveratrol
  8. Protection of UVB exposure-mediated damages in normal human epidermal keratinocytes by resveratrol: involvement of nuclear factor kappa-B pathway
  9. Enhancement of cancer therapeutic effects of ionizing radiation by resveratrol
  10. Conclusions
  11. References

Chronic UVB radiation exposure disrupts the epithelial structure of skin and expands premalignant clones which undergo further genomic changes leading to skin cancer (40). Aziz et al. studied the protective effect of resveratrol against chronic UVB exposure-mediated damages to SKH-1 hairless mouse skin (7). This animal model of multiple UVB exposures (180 mJ/cm2, twice weekly for 28 weeks) represents a UVB initiation-promotion protocol. Employing this model, in this study, resveratrol (25 or 50 μmol/0.2 mL acetone per mouse) was topically applied to mouse skin either prior to or 5 min after each exposure to UVB radiation. The mice were followed for skin tumorigenesis and were euthanized at the termination of experiment for molecular studies (7). The data from this study demonstrated that chronic UVB exposure resulted in a variety of tumors including squamous cell carcinoma, Bowen’s disease, invasive carcinoma’s in situ and actinic keratoses on the mouse skin; whereas topical application of resveratrol to mouse skin (both pre- and post-UVB treatment) resulted in a highly significant inhibition in tumor incidence and multiplicity as well as a delay in the onset of tumorigenesis (7). Importantly, resveratrol treatment was found to reduce the incidence of actinic keratosis (which are regarded as precancerous lesions) suggesting that resveratrol might be inhibiting the malignant conversion of premalignant conditions to a neoplasm (7). Interestingly, both pre- and post-treatment of resveratrol were found to impart equal protection against UVB-mediated damages which suggests that resveratrol’s protective ability may not be sunscreen effects (7).

Further, the authors determined the effect of chronic UVB exposures on protein and mRNA levels of the inhibitor of apoptosis protein survivin. Their data demonstrated a significant up-regulation of survivin both at protein and mRNA levels in response to chronic UVB exposures whereas resveratrol treatment attenuated this response (7). Further, chronic UVB radiation resulted in up-regulation of the phospho-survivin Thr34 protein concurrent with down-regulation of the proapoptotic Smac/DIABLO protein in skin tumors, and resveratrol treatment was found to reverse these responses (7). As the survivin-pathway plays a critical role in apoptotic machinery, Aziz et al. determined the involvement of apoptosis in the prevention of photocarcinogensis by resveratrol. Interestingly, chronic UVB exposure was found to cause an induction of apoptosis in mouse skin, whereas treatment of the skin with resveratrol resulted in a further enhancement of the apoptotic response (7). This study demonstrated that resveratrol imparts a strong chemopreventive effect against chronic UVB exposure-mediated damages including skin carcinogenesis in a mouse model of photocarcinogensis that possesses relevance to human skin cancers (7). This study also suggested that chemopreventive effects of resveratrol may be mediated, at least in part, by negative modulation of survivin pathway (7). On the basis of this work, the authors suggested that it may be useful to design a resveratrol-containing emollient or patch, as well as sunscreen and sun-care products for prevention of skin cancer and other conditions, which are caused by UVB radiation.

Protection of UVB exposure-mediated damages in normal human epidermal keratinocytes by resveratrol: involvement of nuclear factor kappa-B pathway

  1. Top of page
  2. Abstract
  3. Introduction
  4. Resveratrol: a potential chemopreventive agent
  5. Protection of acute UVB exposure-mediated damages by resveratrol
  6. Protection of multiple UVB exposure-mediated damages by resveratrol
  7. Protection of photocarcinogenesis by resveratrol
  8. Protection of UVB exposure-mediated damages in normal human epidermal keratinocytes by resveratrol: involvement of nuclear factor kappa-B pathway
  9. Enhancement of cancer therapeutic effects of ionizing radiation by resveratrol
  10. Conclusions
  11. References

Only few studies have evaluated the mechanism of photoprotective effects of resveratrol against UVB exposure-mediated damages. It is known that skin cells perpetually exposed to solar UV radiation may rely on the transcription factor nuclear factor kappa-B (NF-κB) for protection and survival (41–43). NF-κB is known to play a critical role in the pathogenesis of hyperproliferative skin conditions including cancer (44–46). Adhami et al. (47) determined the involvement of NF-κB in resveratrol-mediated protection of human skin keratinocytes from the adverse effects of UVB radiation. This study demonstrated that UVB (40 mJ/cm2) exposure led to a significant activation of NF-κB/p65 in the normal human epidermal keratinocyte (NHEK), whereas a pretreatment of NHEKs with resveratrol resulted in a significant dose as well as time-dependent down-modulation of UVB-mediated NF-κB activation (47). Further, resveratrol also inhibited the UVB-mediated up-regulation inhibitory kappa-B kinase (IKK) levels, in a dose- as well as time-dependent fashion (47). IKK is known to interact with IκBα and phosphorylate it which triggers degradation of IκBα and activation of NF-κB. The authors further demonstrated that UVB exposure significantly decreased IκBα levels in the cytosol, whereas pretreatment with resveratrol was found to reverse this UVB response (47). Furthermore, UVB exposure of NHEK cells increases phosphorylation of IκBα at serine-32, whereas resveratrol pretreatment results in a significant inhibition of IκBα phosphorylation (47). Based on these data, the authors suggested that the NF-κB pathway plays a critical role in the chemopreventive effects of resveratrol against UVB radiation damages (Fig. 2).

Skin pigmentation is widely regarded as an effective defense mechanism against UV-mediated damages (48,49). The microphthalmia-associated transcription factor (MITF) is involved in melanocyte development and survival, but its role in UVB-mediated pigment production is not well understood (50). In a study by Lin et al. (51), resveratrol (30 μg/mL) was shown to inhibit UVB-induced (30 mJ/cm2) MITF promoter activity in B16 murine melanoma cells. Because other strong antioxidants did not affect MITF promoter activity, it could be suggested that the antioxidant property of resveratrol is not specifically involved in MITF transcription. In this study, resveratrol was also found to have an inhibitory effect on tyrosinase and Tyrp1 promoter activity along with tyrosinase activity, which could be rescued by MITF expression (51). This data suggested that resveratrol, along with MITF, could be used to alter skin pigmentation and guard against UV-mediated damages.

Enhancement of cancer therapeutic effects of ionizing radiation by resveratrol

  1. Top of page
  2. Abstract
  3. Introduction
  4. Resveratrol: a potential chemopreventive agent
  5. Protection of acute UVB exposure-mediated damages by resveratrol
  6. Protection of multiple UVB exposure-mediated damages by resveratrol
  7. Protection of photocarcinogenesis by resveratrol
  8. Protection of UVB exposure-mediated damages in normal human epidermal keratinocytes by resveratrol: involvement of nuclear factor kappa-B pathway
  9. Enhancement of cancer therapeutic effects of ionizing radiation by resveratrol
  10. Conclusions
  11. References

Radiation is an established therapeutic modality for several types of cancers. Radiotherapy is limited due to its severe toxicity towards normal cells at high dose while having only minimal effect on cancer cells at low doses. Therefore, the search for agents and modalities that could increase the sensitivity of tumors cells to radiation is warranted. In a recent study, Zoberi et al. (52) determined whether or not resveratrol can modulate the cellular response of cancer cells to ionizing radiation. The effect of pre-treatment of resveratrol on ionizing radiation-mediated modulations in clonogenic cell survival was studied in human cervical cancer HeLa and SiHa cell lines. The data demonstrated that pre-treatment with resveratrol enhanced ionizing radiation exposure-mediated tumor cell killing in a dose-dependent manner (52). Further, resveratrol pretreatment also inhibited cell division and caused a cell cycle arrest in the S-phase (52). Based on the data, the authors suggested that resveratrol alters both cell cycle progression and the cytotoxic response to ionizing radiation in cervical tumor cell lines (52).

In another study, Baatout et al. (53) examined resveratrol’s ability to sensitize cancer cells to X-ray irradiation in HeLa cells, chronic myeloid leukemia K-562 cells and multiple myeloma IM-9 cells. The effects of up to 200 μM resveratrol and/or X-ray irradiation (0–8 Gy) treatments were determined on cell viability, cell morphology, cell cycle distribution and apoptosis (53). Concomitant treatment with resveratrol and X-ray irradiation was found to result in a synergistic antiproliferative effect at the highest resveratrol concentration (200 μM) (53). In a more recent study, Baatout et al. (54) showed increased radiation sensitivity of the eosinophilic EOL-1 leukemia cell line with resveratrol treatment. Similar to their previous study, simultaneous treatment of resveratrol and X-ray irradiation resulted in a synergistic decrease of cell proliferation concurrent with a synergistic increase in apoptosis and necrosis. These studies suggested that resveratrol could act as a radiation sensitizer in several cancer cell types. However, the concentrations of resveratrol used in these studies appear to be very high and physiologically difficult to be achieved. Therefore, in vivo studies in appropriate models are needed to further investigate the usefulness of this approach.

A recent study by Scarlatti et al. (55) showed that resveratrol sensitizes human prostate carcinoma DU145 cells to ionizing radiation-induced cell death. A synergistic antiproliferative response was found to occur between resveratrol and ionizing radiation against DU145 cells (55). Resveratrol also increased ionizing radiation-induced ceramide accumulation, through promotion of its de novo biosynthesis. Ceramide is a component of complex sphingolipids and mediates intracellular events such as proliferation, differentiation, senescence and cell death (56). This suggested that ceramide could be an effective mediator of the anticancer potential of the combination of resveratrol and ionizing radiation in DU145 cells (55).

Fiore et al. (57) used lymphoblastoid cells AHH-1 to study the induction of DNA breaks using the Comet assay and the induction of apoptosis and cell cycle modulation through flow cytometric analysis after cells were treated with resveratrol and X-rays. This study showed that resveratrol caused apoptosis and S-phase cell cycle arrest (57). Further, resveratrol mitigated the apoptotic clearance of irradiated cells and prevented the G2-phase cell cycle arrest induced by X-rays (57). These studies suggest that resveratrol may be a useful agent in enhancing therapeutic response of ionizing radiations against cancer cells (Fig. 1). However detailed studies, especially in preclinical animal models, are required to validate the relevance of in vitro observations to relevant in vivo situations.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Resveratrol: a potential chemopreventive agent
  5. Protection of acute UVB exposure-mediated damages by resveratrol
  6. Protection of multiple UVB exposure-mediated damages by resveratrol
  7. Protection of photocarcinogenesis by resveratrol
  8. Protection of UVB exposure-mediated damages in normal human epidermal keratinocytes by resveratrol: involvement of nuclear factor kappa-B pathway
  9. Enhancement of cancer therapeutic effects of ionizing radiation by resveratrol
  10. Conclusions
  11. References

The available experimental data suggests that resveratrol could be a useful chemopreventive agent for UV radiation-mediated damages including skin cancer. It appears that the protective effects of resveratrol are mediated via its antioxidant potential and its ability to modulate cell cycle and apoptosis signaling pathways as shown in Fig. 2. Thus, based on the available literature, it is conceivable to design a resveratrol-containing emollient as well as sunscreens and skin-care products for the prevention of skin cancer, premalignant conditions (such as actinic keratoses) as well as other adverse effects including skin aging. Limited studies have also suggested that resveratrol may be useful for enhancing the therapeutic response of ionizing radiations against certain cancer cells, indicating that resveratrol may be used as a complimentary approach to enhance the therapeutic efficacy of existing anticancer modalities.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Resveratrol: a potential chemopreventive agent
  5. Protection of acute UVB exposure-mediated damages by resveratrol
  6. Protection of multiple UVB exposure-mediated damages by resveratrol
  7. Protection of photocarcinogenesis by resveratrol
  8. Protection of UVB exposure-mediated damages in normal human epidermal keratinocytes by resveratrol: involvement of nuclear factor kappa-B pathway
  9. Enhancement of cancer therapeutic effects of ionizing radiation by resveratrol
  10. Conclusions
  11. References
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