Photodermatology, Photoimmunology & Photomedicine


Melatonin’s protective effect against UV radiation: a systematic review of clinical and experimental studies Cecilie Scheuer, Hans-Christian Pommergaard, Jacob Rosenberg & Ismail Gögenur

Department of Surgery, Herlev Hospital – University of Copenhagen, Herlev, Denmark.

Key words: erythema; melatonin; nonmelanoma skin cancer; UV-induced cellular damage; UV-induced DNA-damage; UVR

Correspondence: Miss Cecilie Scheuer, Department of Surgery D Herlev Hospital, DK-2730 Herlev, Denmark. Tel: +4522162309 Fax: +4538683602 e-mail: [email protected]

Accepted for publication: 1 October 2013

Conflicts of interest: None declared.

SUMMARY Background Ultraviolet (UV) radiation is the main etiologic factor for skin cancer. The endogenous hormone melatonin has been proposed to have protective effects against sunlight. Aim The aim of this review was to evaluate melatonin’s protective effects against UV radiation and to clarify the cellular mechanisms behind this effect. Method Medline, Embase and Cinahl were searched up to January 2013 to identify studies evaluating melatonin’s protective effect against UV radiation (UVR)induced skin erythema in humans and damage on a cellular level. Results Four human studies have investigated melatonin’s protective effect on UVRinduced skin damage. Melatonin was shown to have protective effects when applied before UVR, but no effect if applied after exposure. A total of 16 experimental studies evaluated melatonin’s protective effect against UVRinduced damage to cellular structures and pathways. Discussion/Conclusion The protection against UVR-induced skin damage was conducted by melatonin acting directly as an antioxidant, and indirectly by regulating gene expression and inducing a DNA stabilizing effect. As these results were obtained using artificial UVR and without investigating possible side effects, studies using natural sunlight and evaluating possible side effects of topical melatonin administration are warranted. Photodermatol Photoimmunol Photomed 2014; 30: 180–188


© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd doi:10.1111/phpp.12080

Melatonin’s UVR protective effect

Over the last decade, the incidence of skin cancer has increased, especially for nonmelanoma skin cancer (1, 2). In addition, there is an emerging group of high-risk patients treated with immunosuppressive medicine having increased risk of developing nonmelanoma skin cancer (3–5). Ultraviolet radiation (UVR) from sun exposure is known as the main etiologic factor for skin cancer (6–9). The most common DNA damage induced by UVR is the development of cyclobutan dimers. Furthermore, UVR induces mutations in the p53-gene, resulting in loss of its tumor-inhibiting function (10–13). Another key role in the UVR-mediated damage to DNA is the generation of reactive oxygen species (ROS), which are also involved in skin ageing and carcinogenesis (14). Melatonin is known as the main secretory product of the pineal gland and was for several decades considered as a regulator of reproduction but is now also recognized to have great influence on circadian rhythms (15). Furthermore, in the past years it has been acknowledged that melatonin possesses other actions. Melatonin has, for example, been shown to be the most potent endogenous antioxidant in our organism (16–19). Melatonin conducts its antioxidative effect through acting as a direct radical scavenger (18) and by inducing upregulation of gene expression and activity of several antioxidative enzymes, thereby enhancing the cells first line of defense against oxidative damage (20–22). Melatonin has a highly lipophilic structure and is thereby able to penetrate cell membranes and can affect both extra- and intracellular structures (23). Mitochondria, which are a component of every cell, are considered the main source of free radicals in human cells, where excess free radical (ROS) generation is proposed to be a consequence of impairment of the electron transport chain (ETC) (24). UVR induces generation of ROS, which rapidly react with different macromolecules such as proteins and lipids, thus inducing mitochondrial membrane damage and thereby also impairment of ETC (25, 26). Melatonin reduces electron leakage from mitochondria by stimulating the activities of the respiratory chain complexes (26–28). As mitochondrial dysfunction can lead to ATP depletion, depolarization and initiation of apoptotic processes, it is possible that some of the protective effects of melatonin are a result of the actions occurring through the influence of melatonin on mitochondria (29–31). Due to the antioxidant effect and stabilizing effect on various cell structures (32, 33), melatonin may be a promising candidate as a new and effective sun protective agent. The aim of this review was to evaluate the protective effects of melatonin against UVR-induced damage and clarify the cellular mechanisms behind this effect. Photodermatol Photoimmunol Photomed 2014; 30: 180–188 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

METHODS This review was conducted according to the PRISMA guidelines (34). The literature search was performed in January 2013 on Medline (1946 to 2013), Embase (1918 to 2013) and CINAHL (1981 to 2013). Studies were identified using the search terms: ((melatonin)) AND ((((((((UV)) OR (UV light)) OR (erythema)) OR ((sun exposure) AND skin)) OR (sunscreen)) OR (sun damage)) OR (UV damage)). The search terms were used as all fields. Prior to constructing the search strategy the MESH database was searched for relevant MESH terms. There were no restrictions on the year of publication. Only papers written in English or Scandinavian language were included. Additional studies were identified from references from the included studies. Eligibility assessment of abstracts was performed in an unblinded standardized manner by the principal author (C. S.). The study selection process was conducted according to the PRISMA guidelines (34) (see Fig. 1). Relevant papers were included in the systematic review based on the following eligibility criteria: • Study design: Randomized clinical trials. • Participants: Healthy volunteers. • Intervention: Topical application of melatonin in various doses as prevention against UV-induced erythema and damage to cellular structures and DNA. • Control: The intervention had to be compared with a control group receiving topical treatment with vehicle or no treatment. • Outcome: Primary outcome for human studies was effect of topical treatment with melatonin on UV-induced erythema from any UV source (natural or artificial) evaluated by chromatography or the FroschKligman scale (35). In addition to the clinical studies, experimental in vitro studies were included, which had the effect of melatonin against UV-induced cellular damage as primary outcome. • Data extraction: Data extracted from the included studies were year of publication, total number of patients and their respective allocation, specification of the intervention and the control substances, timing of the intervention in relation to UV exposure, melatonin dose used, skin area receiving application with melatonin, effect on UV-induced erythema evaluated with chromatography or Frosch-Kligman scale (35). Effects on cellular parameters included cell viability, generation of radical oxygen species, mitochondrial membrane potential, gene expression, apoptosis, caspase activity, cytochrom C release, DNA synthesis and DNA damage. 181

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Fig. 1. Flow diagram over literature search according to PRISMA guidelines.

Table 1. Effect of topical application of melatonin against UV-induced erythema



Number of included participants

Melatonin dose (%)

Skin area of cream application

Application before UVR exposure

Significant effect on induction of erythema

Bangha et al. (20) Dreher et al. (22) Fischer et al. (21)


20 12 20

0.5 2.5 0.5

5 cm2 × 4 2.25 cm2 × 6 0.4 cm2 × 6

Yes Yes No/Yes†

Yes Yes Only the dose applied before UVR No

Dreher et al. (23)




2.25 cm2 × 9


Time-response study, where melatonin was applied both before and after ultraviolet exposure.

Data were retrieved directly from reviewed studies without data transformation. Outcome values were retrieved and presented with information of significant effects (P < 0.05).

tered alone or in combination when applied after exposure to UVR. This was investigated both with single application immediately after exposure, and multiple applications 30 min, 1 h and 2 h after irradiation.


Application of melatonin prior to UVR

Human studies (see Table 1) Four studies investigating melatonin’s effect on erythema induced by UVR in humans were included. Two studies investigated the effect of melatonin alone (36, 37), and two studies investigated the effect of melatonin in combination with vitamin C and vitamin E (38, 39). Application of melatonin after UVR

Fischer et al. (37) showed that cream containing 0.5% melatonin had no effect when applied after UVR. This is in accordance with Dreher et al. (39), who showed no significant effect of melatonin, vitamin E or vitamin C adminis182

Dreher et al. (38) also investigated the protective effects of melatonin, vitamin E and vitamin C either alone or in combination when applied before exposure to UVR. They found that topical application of melatonin led to a dose-dependent inhibition of erythema measured with chromatography. However, the formulation containing 1% melatonin was less effective in preventing erythema compared with the formulation containing 2.5% melatonin. Furthermore, they showed that the combination of melatonin with vitamin C and E had an even greater suppressive effect on the erythema, than the three substances applied alone. Bangha et al. (36) conducted a dose–response study where the aim was to find the lowest dose of melatonin, Photodermatol Photoimmunol Photomed 2014; 30: 180–188 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Melatonin’s UVR protective effect

Table 2. Effect of topical application of melatonin against UV-induced cellular damage

Study Yamamoto and Mohanan (59) Nickel et al. (40) Fischer et al. (43) Ryoo et al. (41) Lee et al. (42) Fischer et al. (44) Fischer et al. (45) Fischer et al. (46) Luchetti et al. (47) Cho et al. (52) Luchetti et al. (48) Fischer et al. (54) Izykowska et al. (49) Izykowska et al. (50) Fischer et al. (56) Kleszczynski et al. (51)

Cell viability

Generation of ROS

Mitochondrial menbrane potential


Altered gene expression

Caspase activity/realease of cytochrome c

DNA synthesis

DNA damage ↓

↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑

↑ ↑

↓ ↓ ↓ ↓

↑ ↑ ↑

↓ ↓

↑ ↑

↓ ↓

↑ ↑

↓ ↓ ↓ ↓

↑: Significant increased/upregulation of the cellular parameter. ↓: Significant decreased/downregulation of the cellular parameter.

that induced a statistical significant reduction in erythema after exposure to UVR. They found this to be solutions containing 0.5% melatonin.

Sixteen experimental studies were included, and these studies measured a broad range of cellular mechanisms (Fig. 2).

single- and double-stranded DNA breaks, DNA-protein cross-links, lipid peroxidation, protein degradation and mitochondrial damage (25, 53). Mitochondrial damage activates the intrinsic pathway of apoptosis (26). Five out of the 16 included studies measured the generation of radical oxygen species after UVR exposure (43–45, 48, 52). All found that the increased generation of radical oxygen species after UVR exposure was decreased by treatment with melatonin.

Cell viability

Mitochondrial membrane potential

Cell viability was assessed by the tryphan blue staining method. UVR exposure induced decreased cell viability. Twelve out of the 16 studies assessed cell viability and all found that the decrease in cell viability was prevented by melatonin treatment (40–51).

The alterations in mitochondrial membrane potential were detected by use of cytofluorometric analysis (48, 51, 54) and malondialdehyde assay (41). UVR causes reduction in mitochondrial membrane potential leading to mitochondrial membrane damage and thereby activation of the intrinsic pathway of apoptosis. Five out of the 16 studies investigated the influence on the mitochondrial membrane induced by UVR (41, 47, 48, 51, 54) and all found a protective effect of melatonin.

Cellular studies (see Table 2)

Generation of ROS

Generation of ROS was measured using chemiluminescence technique (43–45) and flow cytometry (48, 52). UVR has been shown to induce formation of ROS. When ROS is generated in an amount that overwhelms the body’s antioxidant defense mechanisms, a condition of ‘oxidative stress’ is created. The free radicals rapidly react with many biological macromolecules such as nucleic acids, proteins and lipids, and induce nucleotide damage, Photodermatol Photoimmunol Photomed 2014; 30: 180–188 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd


Most studies assessed the degree of apoptosis with TUNEL plots (41, 46), cytofluorometric technique (51) and flow cytometry (47). Apoptosis is a programmed form of cell death that physiologically plays a role as a defense 183

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Fig. 2. Schematic figure illustrating the cellular structures that are affected by UVR and melatonin’s possible mechanisms of effect against the UV-induced cellular damages.

mechanism to remove infected, mutated or damaged cells (55). UVR exposure induces damage to a wide range of cellular structures creating damaged cells that undergo apoptosis whereby the rate of apoptosis is increased. Five of the 16 included studies measured apoptosis (41, 42, 46, 47, 51) and found that the increase in apoptosis due to UVR was opposed by the treatment with melatonin.

Gene expression

Alterations in gene expression were found with microarray analysis (52), flow cytometry (41) and PCR technique (42, 56). Four studies investigated alterations in gene expression induced by exposure to UVR (41, 42, 52, 56). Common for all studies were that they found an upregulation of apoptosis regulator genes, cancer-related genes, especially in RAS oncogene family, and oxidative stress response genes when cells were exposed to UVR. In the presence of melatonin, upregulation of apoptosis regulator genes, cancer-related genes, cell cycle regulator genes, oxidative stress response genes and signal transducer genes were prevented. 184

Caspase activity and release of cytochrome c

The caspase activity and the release of cytochrome c from mitochondria to the cytosol were assessed by colorimetric technique (52), immunoblot (54), immunocytochemistry (48) and immuneprecipitation (47). The mitochondrial membrane damage induced by UVR leads to the release of cytochrome c from mitochondria into the cytosol where it triggers the formation of the apoptosome (57). The only known function of the apoptosome is the recruitment and activation of caspase 9, which initiates apoptosis (58). Four studies measured caspase activity under UVR exposure (47, 48, 52, 54). The studies all found increased activity of caspases, and increased release of cytochrome c from mitochondria into the cytosol after UVR exposure, and these alterations were opposed by the treatment with melatonin. DNA synthesis

DNA synthesis was measured by incorporation of a radioactive thymidine analog (40, 46). Two studies evaluated the effects on DNA synthesis in response to UVR (40, 46) Photodermatol Photoimmunol Photomed 2014; 30: 180–188 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

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and found that the rate of DNA synthesis was decreased by UVR exposure, and this decrease was prevented by the treatment with melatonin. DNA damage

DNA damage was measured by use of immunohistochemical assessment of 8-OHdG (56) and gel electropherese (59). Oxidative stress is known as the key factor in generation of UVR-mediated oxidative DNA damage represented by the formation of 8-OHdG (13). Two studies evaluated DNA damage after UVR (56, 59), and found that the amount of oxidative damaged DNA was decreased by treatment with melatonin.

DISCUSSION There is convincing evidence that melatonin has a protective effect against UVR-induced erythema in humans when applied before UVR. Results from experimental studies indicate a possible protective effect of melatonin against UVB-induced damage through various mechanisms. Skin cancer is one of the most common forms of cancers worldwide, with an ongoing increase in the incidence through the last decades (2, 60). It has been proven that nonmelanoma skin cancer results from the cumulative sun exposure throughout life (61), and that effective sun protection can prevent the development of malignant melanoma and nonmelanoma skin cancer (62). Melatonin is a naturally occurring hormone that was first identified as the primary secretory product of the pineal gland and is of great importance in regulating circadian rhythms. The last decades of investigation has revealed that melatonin is also produced in the skin (63, 64), where it is proposed to have an important role in the protection against UVR-induced damage. This hypothesis is supported by the presence of functionally active melatonin receptors in membrane, cytosol and nuclei in cells of the skin, suggesting the skin to be a major target for melatonin (65, 66). Because of its highly lipophilic properties, melatonin can penetrate easily through the cellular membranes and therefore is able to effectively protect intracellular structures such as enzymes, proteins, lipids, mitochondria and nuclei against oxidative damage (26, 29). Furthermore, melatonin seems to have a tendency to accumulate in the mitochondria and nuclei, this accumulation being due to regulatory mechanisms and the ability of the mitochondria themselves to produce melatonin (23). Evidence that the mitochondria possess melatonin receptors also supports their role as major targets through which melatonin conducts its effects (67). Photodermatol Photoimmunol Photomed 2014; 30: 180–188 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

As shown in this review, UVR induces a variety of cellular damages of which many are involved in the development of cancer. It is known that UVR induces oxidative stress by the generation of ROS and other free radicals, which have been proven to play a major role in the development of skin cancer (14, 68). ROS induces damages to several intracellular structures by mechanisms as lipid peroxidation, formation of 8-OHdG representing oxidatively damaged DNA with the ability to induce G : C to T : A transversions, DNA single- and double-strand breaks and DNA-protein cross-linking (25, 53). These damages lead to genomic instability with the risk of tumor development. Melatonin has a direct protective effect toward these damages induced by ROS as a potent antioxidant by scavenging free radicals and indirectly by stimulating antioxidant enzymes (69). Furthermore, it has been shown (52) that melatonin induces downregulation of the gene expression of enzymes that are involved in the generation of oxidative stress, and that melatonin enhances antioxidative enzyme gene expression (56). Also the metabolites produced during melatonins metabolism, N1-acetylN2-formyl-5-methoxykynuramine (AFMK) and N[1]acetyl-5- methoxykynuramine, have themselves shown to contribute with antioxidant effects (70), which enables melatonin and its metabolites to exert continuous protection referred to as the free radical scavenger cascade (71–73). Apoptosis is increased by UVR. Recently, it has been recognized that the UVR-induced increase in apoptosis is mostly because of increased stimulation of the intrinsic pathway of apoptosis. A decreased rate of apoptosis after UVR exposure is seen in cells treated with melatonin (41, 42, 46, 47, 51), and one might argue that decreased apoptosis could lead to the survival of mutagenic cells. An argument against this theory is the fact that melatonin opposes damages to cell structures on many levels such as decreased DNA damage, decreased generation of ROS and maintaining mitochondrial membrane potential, thereby maintaining viable cells by preventing apoptosis. Furthermore, it has been shown that melatonin has a positive effect on long-term cell survival in a colony-forming assay (46), which is biologically more relevant in terms of cell survival, proliferation and formation of adherent cell clones. Melatonin has also been shown to have different effects on apoptosis in different cells; preventing apoptosis in immune cells and normal cells, and increasing apoptosis in cancer cells (74). UVR induces oxidative DNA damage in cells. Oxidative damage of DNA results in the production of 8-OHdG, which can be used to recognize oxidatively damaged DNA 185

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(56). The importance of 8-OHdG is, that it can pair adenine instead of cytosine during DNA-replication thereby causing G : C to T : A transversions. High levels of 8-OHdG is observed in various kind of human and animal cancers (68). Melatonin prevents the increase in 8-OHdG, thereby preventing potential failure in DNA replication (56). Sunburn erythema is a well-known acute cutaneous response to UVR, caused by an inflammatory reaction in the skin. An association between epithelial cancer and inflammation has been established (75, 76), and this association is supported by the findings that mice deficient in tumor necrosis factor alpha (TNF-α) are resistant to skin carcinogenesis, proving that an intact TNF-signaling pathway is required for induction of skin tumors (77, 78). Tumor necrosis factor is a pro-inflammatory cytokine and a major inducer of NFκB, a key regulator of oncogenesis. Activation of NFκB promotes cellular proliferation and inhibits apoptosis thereby counteracting p53 and favor cancer development (79). Melatonin has been shown to have anti-inflammatory effects by regulating a number of pharmacological targets, including iNOS, COX-2 and cytokines, such as TNF-α and adhesion molecules (80). Melatonin has also been shown to downregulate signal transduction pathways, including the NFκB pathway (80). Part of the reductive effect, that melatonin conducts on UV-induced erythema, may be due to its antiinflammatory effect. As the insight in the role of immunity in the pathogenesis of many diseases has developed through the past years, the use of immunosuppressive medicine on a broad range of diseases has been introduced. Thereby, a group of patients with high risk of developing nonmelanoma skin cancer has evolved (4, 5). These patients who are constantly immunosuppressed have highly increased risk of developing nonmelanoma skin cancer (81–83). It can be hypothesized that melatonin may be beneficial for these

patients, because melatonin in contrast to standard sun protection performs its sun protective effect by regulating intracellular mechanisms and conducting a DNA stabilizing effect, which may inhibit cancer development. However, these effects have not yet been shown in experimental or clinical studies. Another group of high-risk patients are people with precursor lesions such as actinic keratoses. It has been shown that these lesions have high risk of evolving into regular skin cancer in case of insufficient sun protection (84). It remains to be shown if topical or systemic melatonin treatment may be beneficial in such cases. All the human studies included in this review used an artificial UV source. The percentage of UVB rays in these UV sources is much higher than in natural sunlight (36– 39, 85). For a realistic evaluation of melatonin’s sun protective effect and potential clinical use, studies using natural sunlight have to be conducted.

CONCLUSION Melatonin has sun protective effects both in human and cellular studies. Nevertheless, to answer the question if melatonin can be used as a sun protective agent in the clinical setting, further studies are needed to evaluate melatonin’s sun protective effect with use of natural sunlight. It is also of great importance to identify the optimal concentration of melatonin that would be most effective in reducing UVR damage to the skin. Future studies should also investigate whether application of melatonin on large skin areas will result in adverse reactions or sedative/ cognitive side effects.

ACKNOWLEDGEMENT Illustrator Caroline Heje-Thon contributed illustration.

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Photodermatol Photoimmunol Photomed 2014; 30: 180–188 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Melatonin's protective effect against UV radiation: a systematic review of clinical and experimental studies.

Ultraviolet (UV) radiation is the main etiologic factor for skin cancer. The endogenous hormone melatonin has been proposed to have protective effects...
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