Skin cancer prevention
More can be done to prevent skin cancer than shield against excessive exposure to ultraviolet radiation. There is a growing body of evidence supporting the effectiveness of substances taken internally for skin protection and health. Consider a paper published in the journal Photochemical & Photobiological Sciences in which the authors observe:
"Epidemiological, clinical and laboratory studies have implicated solar ultraviolet (UV) radiation as a tumor initiator, tumor promoter and complete carcinogen, and their excessive exposure can lead to the development of various skin disorders including melanoma and nonmelanoma skin cancers. Sunscreens are useful, but their protection is not adequate to prevent the risk of UV-induced skin cancer...Chemoprevention refers to the use of agents that can inhibit, reverse or retard the process of skin carcinogenesis...A wide variety of botanicals, mostly dietary flavonoids or phenolic substances, have been reported to possess substantial anticarcinogenic and antimutagenic activities because of their antioxidant and antiinflammatory properties."
They examined selected chemopreventive including apigenin, curcumin, grape seed proanthocyanidins, resveratrol, silymarin, and green tea polyphenols, against cancer causing UV radiatoin in laboratory and living systems. Having attended to the mechanism of chemopreventive action of these dietary botanicals they concluded:
"We suggest that in addition to the use of these botanicals as dietary supplements for the protection of photocarcinogenesis, these botanicals may favorably supplement sunscreens protection and may provide additional antiphotocarcinogenic protection including the protection against other skin disorders caused by solar UV radiation."
A paper published last year in Archives of Dermatological Research updated the data on polyphenols and other phytochemicals as skin cancer chemopreventive agents with special reference to the effect of suboptimal immunefunction on vulnerability to skin cancer . The authors state:
"Chronic UV radiation exposure-induced skin diseases or skin disorders are caused by the excessive induction of inflammation, oxidative stress and DNA damage, etc.. The use of chemopreventive agents, such as plant polyphenols, to inhibit these events in UV-exposed skin is gaining attention. Chemoprevention refers to the use of agents that can inhibit, reverse, or retard the process of these harmful events in the UV-exposed skin."
They examined data from a number of studies on the photoprotective effects of green tea polyphenols, grape seed proanthocyanidins, resveratrol, silymarin and genistein, particularly in reference to UV-induced skin inflammation, oxidative stress, and DNA damage. The authors conclude:
"The laboratory studies conducted in animal models, suggest that these polyphenols have the ability to protect the skin from the adverse effects of UV radiation, including the risk of skin cancers. It is suggested that polyphenols may favorably supplement sunscreens protection, and may be useful for skin diseases associated with solar UV radiation-induced inflammation, oxidative stress and DNA damage."
Of great interest is a paper published in the journal Cancer Letters that specifically considers the role of UV radiation-induced immune suppression. The authors note:
"Studies of immune-suppressed transplant recipients and patients with biopsy-proven skin cancer have confirmed that ultraviolet (UV) radiation-induced immune suppression is a risk factor for the development of skin cancer in humans. UV radiation suppresses the immune system in several ways. The UVB spectrum inhibits antigen presentation, induces the release of immunosuppressive cytokines, and elicits DNA damage that is a molecular trigger of UV-mediated immunosuppression...Dietary botanicals are of particular interest as they have been shown to inhibit UV-induced immune suppression and photocarcinogenesis."
Their summary of studies investigating the photoprotective efficacy of dietary agents included green tea polyphenols, grape seed proanthocyanidins and silymarin. Based on this body of data they...
"...present evidence that these chemopreventive agents prevent UVB-induced immunosuppression and photocarcinogenesis through: (i) The induction of immunoregulatory cytokine interleukin (IL)-12; (ii) IL-12-dependent DNA repair; and (iii) Stimulation of cytotoxic T cells in the tumor microenvironment. The new information regarding the mechanisms of action of these agents supports their potential use as adjuncts in the prevention of photocarcinogenesis....The supplementation of the use of sunscreens with these dietary agents may provide an effective strategy for the prevention of melanoma and nonmelanoma skin cancers in humans. The dietary botanical agents discussed are considered to be non-toxic and pharmacologically safe for human consumption."
More recently there have been investigations of the chemopreventive properties of specific agents, such as a paper published in Experimental Dermatology on an extract of Curcuma longa (turmeric).
"...[partial purification from C. longa (PPC)] was used to investigate the alpha-melanocyte-stimulating hormone (α-MSH)-stimulated melanogenesis signal pathway...In cells stimulated α-MSH, PPC inhibited cellular melanin contents, tyrosinase activity and expression of melanogenesis-related proteins including microphthalmia-associated transcription factor (MITF), tyrosinase and tyrosinase-related protein (TRP)...was activated by PPC in α-MSH-stimulated B16F10 cells...MEK/ERK or Akt activation by PPC may contribute to reduced melanin synthesis via MITF and its downstream signal pathway including tyrosinase and TRPs in α-MSH-induced melanogenesis."
In other words, the turmeric extract was shown to regulate pathways intrinsic to the production of melanoma in a way that would inhibit its development. More evidence for the inhibitory effect on melanogenesis of curcumin, the principal medicinal extract of turmeric, was recently reported in the journal Phytotherapy Research. The authors observe:
"Plant derived compounds, as potentially safe and effective skin lightening agents (SLAs), have attracted great attention from many researchers. Curcumin is a plant-derived polyphenol, which has been reported to suppress melanogenesis in B16 melanoma cells."
They specifically investigated whether curcumin affects the development of melanoma in cultured human melanocytes. Additionally, they sought to elucidate the molecular mechanisms by assessing the effects of curcumin on melanin synthesis, cellular tyrosinase activity, the expression of melanogenesis-related proteins, tyrosinase, tyrosinase-related protein 1 and 2, and the activation of a number of melanogenesis-regulating signals in human melanoma cells. The data they obtained is very promising:
"The results showed that the melanin content and tyrosinase activity, as well as the expression of melanogenesis-related proteins in human melanocytes, were significantly inhibited by curcumin in a dose dependent manner. In addition, PI3K/Akt/ GSK 3β, ERK and p38 MAPK were activated by curcumin, while inhibitors of these signals attenuated the inhibitory effects of curcumin on melanogenesis."
Thus they concluded..."These results suggest that curcumin inhibits melanogenesis in human melanocytes through activation of Akt/GSK 3β, ERK or p38 MAPK signaling pathways."
And another study just published in the International Journal of Molecular Medicine demonstrates the same findings.
"The present study was designed to assess the potential inhibitory activity of curcumin on the α-melanocyte stimulating hormone (α-MSH)-stimulated melanogenesis signal pathway in B16F10 melanoma cells. The molecular mechanism of curcumin-induced inhibitory activity on the α-MSH-stimulated melanogenesis signal pathway, including expression of melanogenesis-related proteins and activation of melanogenesis-regulating proteins, was examined in B16F10 cells."
The authors report essentially the same effects of curcumin as described in the earlier paper, including the influence of tyrosinase activity, the expression of melanogenesis-related proteins, and melanogenesis-regulating signals. They state in conclusion:
"Our results suggest that the suppressive activity of curcumin on α-MSH-stimulated melanogenesis may involve the down-regulation of MITF and its downstream signal pathway through the activation of MEK/ERK or PI3K/Akt."
Evidence has been accumulating for some time that green tea polyphenols also protect against skin carcinogenesis. A paper published in Photodermatology, Photoimmunology & Photomedicine reported that green tea constituents protect against UV-induced DNA damage. The authors state:
"Antioxidant compounds in green tea may be able to protect against skin carcinogenesis and it is of interest to investigate the mechanisms involved. A study was therefore conducted to determine whether the isolated green tea polyphenol (−)-epigallocatechin gallate (EGCG) could prevent ultraviolet radiation (UVR)-induced DNA damage in cultured human cells."
Of special interest is that...
"This work was then extended to investigate whether drinking green tea could afford any UVR protection to human peripheral blood cells collected after tea ingestion."
They compared DNA damage induced by UVR in cultured human cells with and without EGCG, and then conducted the same assay on peripheral white blood cells isolated from 10 adult human volunteers before and after drinking 540 ml of green tea. What did the data show?
"The in vivo trials of green tea also demonstrated a photoprotective effect, with samples of peripheral blood cells taken after green tea consumption showing lower levels of DNA damage than those taken prior to ingestion when exposed to 12 min ultraviolet A (UVA) radiation."
Thus they conclude:
"The studies showed that green tea and/or some constituents can offer some protection against UV-induced DNA damage in human cell cultures and also in human peripheral blood samples taken post-tea ingestion."
A paper more recently published in the Journal of Photochemistry and Photobiology adds further evidence that green tea can protect against DNA damage from ultraviolet radiation. The authors state:
"Oral ingestion of green tea is a potent dietary source of antioxidant polyphenols. These compounds are of interest as they may be able to provide additional protection to the body to help prevent the deleterious effects of ultraviolet A and visible radiation (UVA/VIS) produced indirectly via reactive oxygen species (ROS) in sunlight exposed skin."
They too exposed white blood cells drawn from healthy human volunteers to UV irradiation after ingestion of green tea and measured the levels of DNA damage. They conclude:
"The findings...indicate that drinking green tea did significantly reduce the genotoxic effects observed in peripheral blood cells 60 min following ingestion when artificially exposed to 12 min of UVA/VIS irradiation in the laboratory. It is postulated that this protection is afforded by the polyphenol compounds (known to be contained within green tea) via scavenging or quenching of the damaging ROS induced by this form of light exposure."
Ellagic acid, another polyphenol found in pomegranate and berries, has also been studied for its ability to reduce skin damage due to UV-B irradiation. The authors of a paper published in Experimental Dermatology state:
"This study examined photoprotective effects of ellagic acid on collagen breakdown and inflammatory responses in UV (ultraviolet)-B irradiated human skin cells and hairless mice. Ellagic acid attenuated the UV-B-induced toxicity of HaCaT keratinocytes and human dermal fibroblasts. Non-toxic ellagic acid markedly prevented collagen degradation by blocking matrix metalloproteinase production in UV-B-exposed fibroblasts."
Interestingly, in regard to wrinkle production ellagic acid...
"...attenuated UV-B-triggered skin wrinkle formation and epidermal thickening...In addition, this compound mitigated inflammatory intracellular cell adhesion molecule-1 expression in UV-B-irradiated keratinocytes and photoaged mouse epidermis."
The skin inflammation due to UV exposure noted in the authors' conclusion is a contributing cause for skin cancer:
"These results demonstrate that ellagic acid prevented collagen destruction and inflammatory responses caused by UV-B. Therefore, dietary and pharmacological interventions with berries [and pomegranate] rich in ellagic acid may be promising treatment strategies interrupting skin wrinkle and inflammation associated with chronic UV exposure leading to photoageing."
Sulforaphane, a compound found in cruciferous vegetables, has also been shown to reduce carcinogenic inflammation as documented in a paper just published in Molecular Carcinogenesis. The authors state:
"Ultraviolet (UV) of sunlight is a complete carcinogen that can burn skin, enhance inflammation, and drive skin carcinogenesis. Previously, we have shown that sulforaphane (SFN) inhibited chemically induced skin carcinogenesis via nuclear factor (erythroid-derived 2)-like 2 (Nrf2)...Since Nrf2 plays critical roles in the anti-oxidative stress/anti-inflammatory responses, it is relevant to assess the role of Nrf2 for photoprotection against...UVB-induced skin inflammation."
To do this they induced skin inflammation by UVB irradiation in two groups of mice, with and without the Nrf2 genes that respond to sulforaphane. What did they find?
"SFN treatment of Nrf2 WT ['wild type', with Nrf2 genes] but not Nrf2 KO ['knockout', without Nrf2 genes] mice restored the number of sunburn cells back to their basal level by 8 d after UVB irradiation. Additionally, UVB-induced short-term inflammatory biomarkers (interleukin-1β and interleukin-6) were increased in the KO mice and UVB-induced apoptotic cells in the KO mice were significantly higher as compared to that in the WT. Taken together, our results show that functional Nrf2 confers a protective effect against UVB-induced inflammation, sunburn reaction, and SFN-mediated photoprotective effects in the skin."
In other words, sulforaphane (SFN) from cruciferous vegetables like broccoli, Brussels sprouts and cabbages activated the Nrf2 genes that conferred protection against UVB-induced inflammation.
While there is evidence that polyphenols, green tea EGCG, curcumin, sulforaphane and other single agents protect against skin cancer, a combination of multiple agents may work best. The authors of a paper published in the journal Dermatologic Surgery note:
"The endogenous antioxidant system of the skin scavenges reactive oxygen species and combats ultraviolet induced oxidative skin damage. Supporting this cutaneous defense system with topical or oral antioxidants may provide a successful strategy for the treatment and prevention of skin cancer."
They undertook a review of the evidence available in 2002 for treatment and prevention of melanoma and nonmelanoma skin cancers using antioxidants and vitamins. Their findings were mixed:
"Review of the literature demonstrates that the administration of synthetic retinoids has not proved beneficial for otherwise healthy patients with nonmelanoma skin cancer. Selenium supplementation has reduced the incidence of several internal malignancies but not of nonmelanoma skin cancer. Synergistic use of β-carotene with vitamins C and E has demonstrated prophylaxis against reactive oxygen radicals involved in nonmelanoma skin cancer and reduced sunburn reactions significantly. 1,25-dihydroxyvitamin D3 analog CB1093 has demonstrated promise as a therapeutic agent in the regression of the early stages of melanoma in specific cell lines."
They support the use of a combination approach:
"Delivery of exogenous antioxidants in combination appears to be a more successful strategy for enhancing the cutaneous antioxidant system than the administration of isolated antioxidants alone. Vitamin D analogs may have a role in the medical therapy of melanoma."
The authors of a paper published recently in the journal Seminars in Cutaneous Medicine and Surgery also assert that combining multiple agents may be significantly more effective than single agents in prevention of UV-induced skin cancer:
"With the incidence of nonmelanoma skin cancer on the rise, current prevention methods, such as the use of sunscreens, have yet to prove adequate to reverse this trend. There has been considerable interest in identifying compounds that will inhibit or reverse the biochemical changes required for skin cancers to develop, either by pharmacologic intervention or by dietary manipulation. By targeting different pathways identified as important in the pathogenesis of nonmelanoma skin cancers, a combination approach with multiple agents or the addition of chemopreventative agents to topical sunscreens may offer the potential for novel and synergistic therapies in treating nonmelanoma skin cancer."
Along these lines a promising study just published in the journal Nutrition and Cancer offers evidence that the multiherbal formulation Zyflamend inhibits melanoma growth. By way of background...
"Though isolated dietary components such as lycopene, resveratrol, and isothiocyanate compounds have been shown to provide limited protection against cancer development, the use of whole herbs and herbal extracts for the treatment of cancer remains of great interest. As suggested by earlier studies, the antiinflammatory activity of many plants available as intact products or as extracts has long been considered for supplemental therapeutics for cancer."
They further observe:
"Zyflamend, a unique multiherbal extract preparation, is a promising antiinflammatory agent that has also been suggested to regulate multiple pathways in cancer progression. As Zyflamend contains ingredients that can suppress tumor cell proliferation, invasion, angiogenesis, and metastasis through regulation of inflammatory pathway products, we hypothesized that this preparation might inhibit melanoma proliferation."
The authors designed their study to test the effect of Zyflamend on melanoma proliferation. They found that...
"Zyflamend inhibits melanoma growth by regulating the autophagy–apoptosis switch. Based on the responsible molecular mechanisms of Zyflamend, our study highlights the importance of the use of herbal preparations for the prevention and treatment of cancer."
Interestingly, two earlier studies published in the same journal report that Zyflamend induces apoptosis (programmed cell death) of prostate cancer cells and inhibits malignant bone destruction and invasion while potentiating cytotoxicity.A sound strategy for skin cancer prevention requires a comprehensive examination of the various possible contributing causes that addresses the unique needs of the individual. That being said, there is ample evidence that beneficial agents are available to play a role in protection from UV-induced irradiation that are worthy of consideration.