Potential use of melatonin in skin cancer treatment: A review of current biological evidence

Abstract

Skin cancer, particularly melanoma, is a leading cause of death worldwide. The therapeutic methods for this malignancy are not effective, and due to the side effects of these treatments, applying an appropriate alternative or complementary treatment is important. According to available data, melatonin as the main product of the pineal gland has oncostatic and antitumoral properties. Also, melatonin acts as an anti‐inflammatory and reactive oxygen species inducer agent which suppresses the growth of tumors. It also has apoptosis induction characteristics through regulating signaling pathways, including heat shock protein 70, nuclear factor‐erythroid 2 p45‐related factor 2 and others. Thus, adding melatonin to chemo‐ and radiotherapy may have synergistic therapeutic effects and increase the survival time in patients with skin cancer. Few clinical studies have evaluated the efficacy of melatonin in skin cancer. Based on the related mechanisms, this review discusses about how melatonin may improve outcomes in skin cancer patients.

According to available data, melatonin as the main product of the pineal gland has oncostatic and antitumoral properties. Also, melatonin acts as an anti‐inflammatory and reactive oxygen species inducer agent which suppresses the growth of tumors. It also has apoptosis induction characteristics through regulating signaling pathways, including heat shock protein 70, nuclear factor‐erythroid 2 p45‐related factor 2 and others.

1. INTRODUCTION

Melanoma is one of the most complexes, aggressive and heterogeneous cancers in the world (Andor et al., 2016). Although this malignancy commonly arises from cutaneous melanocytes, it can also derive from mucosal surfaces, such as genital and gastrointestinal mucosa, oral cavity, and eye uveal tract (Fu, Wu, Zhang, Lian, & Lu, 2017). In the US in 2017, more than 87,000 newly diagnosed patients with melanoma were reported. In addition, approximately 10,000 cancer‐associated mortality occur annually (Abdul‐Karim & Cowey, 2017). Skin phototype, hair color, multiple nevi, family history, and ultraviolet (UV) radiation are known as etiologic factors for this cancer (Hernando et al., 2016; Pfeifer, 2015; Raimondi et al., 2008). Standard treatments including chemotherapy and radiotherapy are not sufficiently effective to significantly increase the survival time of patients with melanoma (Grzywa, Paskal, & Wlodarski, 2017; Keller, Zhang, Li, Schaider, & Wells, 2017). Moreover, during its progression, resistance to cytotoxic drugs occurs leading to the necessity to intensify the therapy. Therefore, searching for either novel therapies or complementary treatments which exert anticancer actions is very important.

Melatonin, as an anticancer agent, is secreted at night by the pineal gland. It is known to regulate seasonal and circadian day–night biorhythms (Bubenik & Smith, 1987; Lerchl & Schlatt, 1993). In addition, recognized physiological functions of melatonin include the modulation of immune system (Carrillo‐Vico et al., 2004; Guerrero & Reiter, 2002), body weight and reproduction (Lincoln, 2006), anti‐jet‐lag and tumor growth inhibitory effects (Fischer et al., 2006; Waterhouse, Reilly, Atkinson, & Edwards, 2007). Melatonin also acts as a direct antioxidant (Fischer & Elsner, 2001; Tan et al., 2002), a drug‐induced chemotoxicity reducing factor (Atessahin et al., 2006; Oz, Erbas, Surucu, & Duzgun, 2006), an antiaging agent (Reiter et al., 1999; Reiter, Tan, Manchester, & El‐Sawi, 2002), an anti‐inflammatory (Esposito & Cuzzocrea, 2010) and antihypertensive substance (Yousaf, Seet, Venkatraghavan, Abrishami, & Chung, 2010). Because of its lipophilic property, melatonin can easily penetrate cellular membrane to protect critical intracellular structures such as DNA and mitochondria from oxidative damages at the places where damage often occurs (Fischer, Scholz, Knoll, Hipler, & Elsner, 2004; Fischer, Zmijewski, Wortsman, & Slominski, 2008). The antitumor activity of melatonin in cancer treatment has been well demonstrated. Numerous studies have shown that melatonin can restrain the autonomous growth of tumors (Altun & Ugur‐Altun, 2007; Blask, Dauchy, & Sauer, 2005; Malhotra, Sawhney, & Pandhi, 2004). Moreover, melatonin has reported effects on duration of the survival time of patients with cancer (Lissoni, 2002; P. Lissoni et al., 1999). To assess the beneficial roles of melatonin in the therapy of skin cancer, based on the available studies, this review evaluates the current knowledge of melatonin effects on skin cancer (Figure 1).

Figure 1.

Schematic representation of targeting different signaling pathways using melatonin is a novel therapeutic strategy in the treatment of skin cancer [Color figure can be viewed at wileyonlinelibrary.com]

2. MELATONIN RECEPTORS IN MELANOMA

MT1 receptor is highly distributed in the skin and is located on the plasma membrane of the cutaneous cells such as the melanocytes, fibroblasts, squamous cell carcinoma, keratinocytes, and melanoma cells (Slominski et al., 2002). The immunoreactivity of MT1 has been detected in granular layer of the epidermis and on keratinocytes of the spinous layer of the human scalp (Slominski et al., 2005). MT2 receptors are also found in malignant and normal melanocytes (Roberts, Wiechmann, & Hu, 2000) and in eccrine sweat glands (Slominski et al., 2005). It has been reported that the melatoninergic system of the skin protect the functional and physical skin integrity against intrinsic dyshomeostatic stimuli and environmental stress. In addition to UV radiation (Slominski et al., 2003), melatonin protects the skin against X‐rays (Kanikkannan, Jackson, Shaik, & Singh, 2001). The inhibition of growth is presumably triggered by melatonin and MT2 activation receptor in human melanoma cells and melanocytes (Roberts et al., 2000).

3. MELATONIN, A REGULATOR OF OXIDATIVE STRESS PATHWAYS IN CELL CANCER

The imbalance between cellular oxidative and antioxidants enzymes as well as overproduction of reactive oxygen species (ROS) in cancer cells have important treatments role. According to this point, Radiation and some chemotherapeutic agents of cancer treatment produce ROS and leads to apoptosis or cancer cell death (Ozben, 2015). In a different studies reported that melatonin therapy also generate ROS and resulting in tumor cells (Ozben, 2015). Increased ROS by melatonin leads to activation of apoptosis pathways such as caspase‐3 in cancer cells (Pariente, Pariente, Rodríguez, & Espino, 2016). In a study reported that melatonin combined with endoplasmic reticulum stress decreased antioxidant enzymes such as SOD in melanoma (H. S. Kim, Kim & Yoo, 2014). Therefore, melatonin may be an appropriate treatment of skin cancer through production of ROS.

4. PROLIFERATIVE ROLE OF MELATONIN FROM UV‐INDUCED DAMAGE VIA HSP70 REGULATION

In addition to DNA damage, UV radiation induces functional alterations such as immunosuppression, apoptosis, and inflammation (activation of inflammatory cytokines) in healthy skin cell (Arad, Konnikov, Goukassian, & Gilchrest, 2007; Kappes, Luo, Potter, Schulmeister, & Runger, 2006). The heat shock protein (HSP) family is a set of molecular chaperones induced in response to physical, chemical and environmental stressors (Morimoto & Santoro, 1998; Wilson et al., 2000). HSP70, as a major member of this protein set, protects different cells from death (De Maio, 2014; Guzhova & Margulis, 2006). HSP70, when released from tumor cells, activate anti‐melanoma T cells in vitro (Castelli et al., 2001). Previous studies have shown that Hsp70 is produced in keratinocytes both in vivo and in vitro (Jonak, Klosner, & Trautinger, 2006; Trautinger, 2001). Additionally, HSP70 affect the cascade of events that trigger programed cell death and includes activation of p53 and JNK, Bax proapoptotic protein translation into mitochondria and downstream proapoptotic caspase activation (Casp‐3 or Casp‐9; Kong et al., 2016).

Based on previous investigations, melatonin downregulates the expression of HSPs including Hsp40, Hsp70, and Hsp90 in rat liver (Catala, Zvara, Puskas, & Kitajka, 2007) and in C6 glioma cells (Esposito et al., 2008) thereby reducing oxidative stress. Moreover, an in vitro study conducted using human skin and cultured keratinocytes, also indicated that melatonin downregulates the expression of Hsp70. The known antioxidative activities of melatonin may provide an additional mode of defense; therefore, the skin cells might not need to express more HSP70 (Kleszczynski et al., 2015).

5. ANTIAPOPTOTIC ROLE OF MELATONIN

Apoptosis is triggered by mitochondrial membrane potential dissipation. UV radiation makes the mitochondrial membrane hyperpolarized leading to cytosolic acidification related to facilitating the translocation of Bax. Notably, Bax, as a proapoptotic molecule in mitochondria, shifts the cells fate toward apoptosis (Kleszczynski, Tukaj, Kruse, Zillikens, & Fischer, 2013). Melatonin prevents the acidification of the cytosol resulting in UV radiation‐induced apoptosis (Goswami & Haldar, 2015). P53 and the associated induced apoptosis are protective manners against tumor formation and skin carcinogenesis induced by UV radiation (Brash et al., 1996). Melatonin also induces both p53, as a tumor suppressor, and its target gene p21 to trigger cell apoptosis (C. H. Kim & Yoo, 2010). Bcl‐2, a protective factor in skin cells, is also downregulated by UV radiation in normal skin cells and also in DNA repair deficient fibroblasts (Isoherranen, Sauroja, Jansen, & Punnonen, 1999). Bcl‐2 levels are amplified due to the antiapoptotic potential of melatonin, as a cell survival signal (Canonico et al., 2013). UV radiation causes impairment of mitochondrial membrane leading to release of cytochrome c into the cytosol with the formation of the apoptosome (Cain, Bratton, & Cohen, 2002). The only identified activity of the apoptosome is the activation and recruitment of caspase 9, which promotes apoptosis (Marek, 2013). Several studies have documented that the increased activity of caspases resulting from UV radiation exposure with the elevated release of cytochrome c from mitochondria. These alterations are all opposed by melatonin. Thus, melatonin inhibits cellular apoptotic activity due to UV radiation and protects the skin against carcinogenesis.

6. MELATONIN, A REGULATOR OF PI3K/AKT/MTOR PATHWAY

The PI3K/Akt/mTOR pathway is especially activated in human melanoma and is considered as a site for therapeutic intervention in the treatments of melanoma (Werzowa et al., 2011; Xie, White, & Mehnert, 2013). A number of reports have shown that the PI3K/Akt/mTOR signaling modulates Bcl‐2 and Bax family proteins expression (Asnaghi et al., 2004; Tirado, Mateo‐Lozano, & Notario, 2005). It was also documented that melatonin combined with tunicamycin or thapsigargin attenuated the proliferation and growth of B16F10 melanoma cells. This combination also significantly upregulated Bax and downregulated Bcl‐2 in melanoma cells. Thus, Bax and Bcl‐2 family proteins impact the proliferation of melanoma cells via MAPK or PI3K/mTOR signaling pathways and may modulate the severity of melanoma and inhibit tumor progression (H. S. Kim, Kim & Yoo, 2014).

7. ANTI‐INFLAMMATORY ROLE OF MELATONIN

The association between inflammation and epithelial cancer has been established (Palli et al., 1998). As a proinflammatory cytokine, tumor necrosis factor α (TNF‐α) is a major inducer of nuclear factor kB (NF‐kB), known to be regulator of oncogenesis. NF‐kB activation causes proliferation and inhibits apoptosis thereby counteracting p53 and favoring cancer progression. It is well known that melatonin has anti‐inflammatory activities via regulating some pharmacological targets, such as cyclooxygenase‐2 (COX‐2), inducible nitric oxide synthase (iNOS), and proinflammatory cytokines including TNF‐α and adhesion molecules. Melatonin also downregulates signal transduction pathways such as the NF‐kB pathway (Lin & Karin, 2003). In vitro, the combination of a melatonin with fisetin enhances the antitumoral effects on melanoma cells by activating the apoptotic signaling by involving the cytochrome‐c/caspase‐dependent pathway and inhibiting the expression of p300/NF‐kB‐mediated iNOS and COX‐2 (Yi et al., 2014). Consequently, anti‐inflammatory activity of melatonin plays an essential role in suppressing malignancy through regulating these related pathways.

8. ANTICANCER ROLE OF MELATONIN

The anticancer functions of melatonin via a direct action or circadian rhythm regulation have been reviewed in depth elsewhere (Mauriz, Collado, Veneroso, Reiter, & Gonzalez‐Gallego, 2013). Antimelanoma effects of melatonin, in both in vitro and in vivo investigations have been demonstrated primarily in rodent models (Slominski & Pruski, 1993; Su et al., 2017). The beneficial effects of melatonin in advanced stage of metastatic melanoma, by either increasing the efficacy of chemo‐/chemoimmunotherapy or by reducing their side effects, have been confirmed (Lissoni et al., 1997). Melatonin attenuate benzo[a]pyrene‐induced squamous cell carcinoma (Lissoni et al., 2002), cutaneous sarcomas (Man'cheva et al., 2011), and papillomas (Zmijewski, Sweatman, & Slominski, 2009) in mice. In comparison to controls, patients with squamous cell and basal cell carcinoma had lower levels of systemic melatonin production (Kumar & Das, 2000). However, there are few clinical trials about the effect of melatonin on the survival of patients.

9. MELATONIN'S METABOLITES AND THEIR TRANSPORTERS IN MITOCHONDRIAL MEMBRANE CONTRIBUTES TO APOPTOSIS INDUCTION IN TUMOR CELLS

Melatonin is metabolized mainly by cytochrome P450 (CYP450) in the liver. CYP450 is a key enzyme for endogenous substrates and drugs metabolism (Guengerich, 2007; Nebert, Wikvall, & Miller, 2013). It has been demonstrated that melatonin was metabolized to 6‐hydroxymelatonin (6‐OH‐Mel) and N‐acetylserotonin (NAS) by CYP1A1 and 2C19, CYP450 isomers, at Phase I metabolism, and most of them were subsequently converted to sulfate conjugates by sulfotransferases in human liver (Jiang et al., 2016; Tian et al., 2015). CPY1B1 is responsible mainly for melatonin metabolism to NAS in the mitochondria of tumor cells. NAS, the main active metabolite of melatonin, induces mitochondrial apoptosis in both si1‐SH‐SY5Y and siCtrl‐SH‐SY5Y cells. Its expression knockdown in mitochondria of tumor cells reduces the mitochondrial concentrations of NAS and decreases melatonin inhibitory effects on the proliferation of cancer cells. Therefore, demethylation to form the NAS is the main way of melatonin metabolism in tumor cells and melatonin‐induced apoptosis is through the mitochondrial CYP1B1‐NAS‐Cyto c pathway (Yu et al., 2018). Melatonin is needed to cross the membrane and penetrates the various cell compartments. It was recently reported that a facilitated diffusion was implicated in transmembrane transportation of melatonin. OAT3 and PEPT1/2, the cellular transporters, were identified to facilitate the melatonin and its sulfation metabolites transmembrane transportation, respectively. Melatonin primarily metabolized to form two Phase I metabolites (NAS and 6‐OM) and corresponding SULT conjugation metabolites (NAS‐S and 6‐OM‐S) observed that melatonin was PEPT1/2 substrate, while NAS‐S and 6‐OM‐S were OAT3 substrates. PEPT1/2 transporters play a key role in the uptake of melatonin in cells. Membrane transportation of melatonin through PEPT1/2 renders its oncostatic activity in tumor cells. PEPT1/2 facilitates melatonin transportation into mitochondria. Melatonin accumulation in mitochondria induced apoptosis of human cancer cell lines of U118 and PC3 (Huo et al., 2017).

10. MELATONIN SAFETY AND LOW TOXICITY MAKE IT AN IDEAL CHOICE AS AN ADJUVANT THERAPY FOR CANCER

Despite all the effectiveness of chemotherapy and radiotherapy in the treatment of malignancies, unfortunately these therapies have adverse effects which reduce the patient's quality of life, and may result in therapy discontinuation (Shapiro, 2016; Turcotte et al., 2017). Thus, it is critical to decline these harmful effects by adding complementary treatments. Both radiosensitization and radioprotective effects of melatonin make it an appropriate candidate for use as an adjuvant treatment in radiotherapy. Also, the natural metabolism of melatonin in human cells leads to low toxicity in comparison with other chemical products such as amifostine (Vasin & Ushakov, 2014). A meta‐analysis involving eight randomized controlled trials conducted by Wang et al. (2012) showed the safety of melatonin even at high doses (20 mg/day). It led to remarkably better survival at 1 year, greater tumor remission and less radiochemotherapy‐associated side effects, including neurotoxicity, thrombocytopenia, and fatigue. Melatonin also induces a decrease in the frequency of chemotherapy‐induced stomatitis, asthenia (P. Lissoni et al., 1999) and cardiotoxicity (C. Kim et al., 2005). One of the probable side effects of melatonin is the trend to produce sleepiness or sedation in some patients. Since antioxidant activity of melatonin is not associated with day time, to avoid sedation, it is better to intake melatonin in the evening.

11. CONCLUSIONS

In response to threatening environmental factors such as UV radiation, human skin cells protect themselves by various mechanisms. Melatonin is protective agent in every organ including the skin where it functions as an ROS generator and lower inflammation. A major anticancer role of melatonin is related to its apoptotic and free radical scavenging properties. Therefore, adding melatonin supplementation to routine medical treatments including surgery, chemotherapy, and radiotherapy, in addition to enhancing their effectiveness, may reduce their related side effects and toxicities leading to increased survival time of patients with skin cancer.

CONFLICTS OF INTEREST

The authors declare that there are no conflicts of interest.

AUTHOR CONTRIBUTIONS

Z. A. contributed in conception, design, and drafting of the manuscript. M. H. P. and M. M. contributed in data collection and manuscript drafting. All authors approved the final version for submission. R. J. R. reviewed the proposal and manuscript, and offered critical comments. Z. A. oversaw the study.