SEARCH

SEARCH BY CITATION

Keywords:

  • cancer;
  • hormone replacement therapy;
  • melatonin;
  • melatonin receptors;
  • osteoporosis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References

Abstract:  Melatonin's therapeutic potential is grossly underestimated because its functional roles are diverse and its mechanism(s) of action are complex and varied. Melatonin produces cellular effects via a variety of mechanisms in a receptor independent and dependent manner. In addition, melatonin is a chronobiotic agent secreted from the pineal gland during the hours of darkness. This diurnal release of melatonin impacts the sensitivity of melatonin receptors throughout a 24-hr period. This changing sensitivity probably contributes to the narrow therapeutic window for use of melatonin in treating sleep disorders, that is, at the light-to-dark (dusk) or dark-to-light (dawn) transition states. In addition to the cyclic changes in melatonin receptors, many genes cycle over the 24-hr period, independent or dependent upon the light/dark cycle. Interestingly, many of these genes support a role for melatonin in modulating metabolic and cardiovascular physiology as well as bone metabolism and immune function and detoxification of chemical agents and cancer reduction. Melatonin also enhances the actions of a variety of drugs or hormones; however, the role of melatonin receptors in modulating these processes is not known. The goal of this review is to summarize the evidence related to the utility of melatonin as a therapeutic agent by focusing on its other potential uses besides sleep disorders. In particular, its use in cancer prevention, osteoporosis and, as an adjuvant to other therapies are discussed. Also, the role that melatonin and, particularly, its receptors play in these processes are highlighted.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References

Melatonin has been shown to play a role in many physiological systems, including those involved in sleep [1], gastrointestinal physiology [2–4], immune defense [5, 6], cardiovascular function [2, 3, 7–9], renal function [2], detoxification [10–12], reproduction [13–15], and retinal [16], as well as bone physiology [17]. Some of these systems regulate peripheral clocks, which, in turn, attempt to synchronize themselves against the master biological clock's pacemaker [18]. With the cloning of the receptors [19, 20] and microarray analyses of select tissues [21–23], it is obvious that melatonin impacts on multiple physiological systems, but how it does remains to be determined.

It is difficult to attribute a specific mechanism to an effect of melatonin on a particular physiological process or in treating disease as melatonin's actions are diverse. For example, as shown in Fig. 1, melatonin can produce effects through receptors [3, 24] or independent of receptors [10–12]. The receptors, once activated by melatonin, can signal through cAMP-dependent cascades, mitogen activated protein kinase cascades [24], and also through estrogen-dependent signaling cascades [8, 25]. The receptors (MT1, MT2) belong to the G-protein coupled receptor class while the MT3 binding site belongs to the quinone reductase 2 family of detoxifying enzymes [26]. Because of the overlap of some signaling cascades to produce the same effect [e.g. inhibition of estrogen receptor (ER) transactivation or detoxification], it is difficult to decipher whether or not these responses are mediated via receptors.

image

Figure 1.  The diverse mechanisms mediated by melatonin within a cell. Melatonin produces effects in a receptor-dependent or independent manner. Melatonin alone and independent of receptors, passes through cell membranes, accumulates within a cell, and inhibits calmodulin or acts in radical detoxification. Detoxification occurs through melatonin's free radical scavenging properties and due to its ability to up-regulate detoxifying enzymes including catalase, superoxide dismutase, and glutathione peroxidase. Melatonin effects via MT3 sites regulating quinone reductase 2 activity are still unclear but may be involved with oxidative/reductive mechanisms through unidentified mechanisms. Melatonin inhibits calmodulin activity by preventing calcium binding and/or by inducing its phosphorylation through PKC alpha. The consequence of calmodulin inhibition by melatonin may result in a reduction in cAMP accumulation through calmodulin-sensitive adenylyl cyclases. This may cause an attenuation of cAMP-dependent signaling cascades, including the activation of cAMP response element binding (CREB) protein and cAMP response element (CRE)-containing genes. Melatonin-mediated reductions in calmodulin activation decrease estrogen receptor (ER) binding to and activation of estrogen response element (ERE)-containing genes. Also, as depicted, melatonin can act via its G-protein coupled receptors, MT1 or MT2 to suppress CREB-induced and/or ER-induced activation of genes. Furthermore, through its activation of MT2 receptors, melatonin activates the mitogen activated protein kinase cascade (MEK/ERK 1/2) and promotes cellular differentiation and retards cellular proliferation. This may occur via autocrine actions of heparin-bound epidermal growth factor (HB-EGF) released following the activation of MT2 melatonin receptors, Gi proteins, matrix metalloproteinases (MMPs) and internalization processes.

Download figure to PowerPoint

The fact that melatonin is a chronobiotic agent means that the timing of the release from the pineal gland or dose may dictate whether the response to melatonin is absent, weak or strong. Melatonin displays different periods of sensitivity as it relates to its effects on phase-shifting circadian rhythms [1, 27]. Perhaps other targets of melatonin (i.e. genes or proteins regulated by melatonin receptors) show similar rhythms. Many genes [22, 23, 28], disease-related entities such as tumors [29] and melatonin (MT1) receptor mRNA [24, 30] exhibit a circadian rhythm (Fig. 2) and some, including cancer cells, express the same clock genes found in the master biological clock [31]. A thorough understanding of the regulatory patterns of melatonin receptors and its targets in response to melatonin or throughout the 24-hr day should be examined. A better understanding of these targets and how melatonin and its receptors play in their physiology will hopefully lead to its regular use in the clinic. To further this stated objective, this review will focus on areas that show promise yet are still not used regularly in the clinical setting.

image

Figure 2.  Schematic showing the variables that may contribute to melatonin's efficacy as a therapeutic agent. For some functions, melatonin has different periods of sensitivity throughout the 24 hr light/dark cycle, that is, at dusk and at dawn as shown by the arrows. Also, in some organs, melatonin receptor density (depicted by the sun symbols), affinity and (perhaps) sensitivity fluctuate throughout a 24-hr period. When melatonin levels are low (during the day), melatonin receptor affinity and density are high. By contrast, when melatonin levels are high (during the night), melatonin receptor affinity and density are low. Thus, to maximize the therapeutic efficacy of melatonin when its actions are receptor-mediated, it may be important to administer melatonin during the period when receptor sensitivity is highest. Many genes fluctuate throughout the light/dark cycle or in a circadian manner as shown. These genes support a role for melatonin and its receptors in cancer prevention, metabolism, host defense, bone metabolism, and cellular differentiation.

Download figure to PowerPoint

Melatonin as a therapy for the prevention of osteoporosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References

Osteoporosis, a disease predominantly associated with aging, occurs following prolonged structural deterioration of the skeletal system. Recent therapies include targeting bone-resorbing osteoclasts by use of bisphosphonates, estrogen, and calcitonin to prevent further bone breakdown. However, these therapies are limited because they do not form bone as is necessary in cases of individuals suffering from severe osteoporosis. One drug is available that stimulates bone-forming osteoblasts (e.g. teriparatide); however, its treatment is limited to 2 yr, it is expensive and has risks associated with its use. Melatonin as a therapy for the prevention and treatment of osteoporosis should be considered. The rationale for its use is described below.

Noctural plasma melatonin levels significantly decline after the age of 50 in both genders [1, 6, 32] perhaps due to neuroaxonal dystrophy of sympathetic innervation of the pineal gland [33]. A correlation between reduced plasma melatonin levels and an increased incidence of bone deterioration as seen in osteoporosis has been examined [17]. In fact, removal of the pineal gland in rats promotes the induction of bone metabolism biomarkers while melatonin exposure suppresses them [34]. Furthermore, light influences the oscillations of these bone markers where a short day induces the expression of these markers and a long day suppresses them [28]. Other associations between melatonin and bone have been observed in the clinic whereby melatonin-related patterned skin pigmentation is commonly seen in certain bone disorders [35].

Melatonin has been shown at the cellular and organismal level to promote osteogenesis and prevent bone deterioration [36–40]. In fact, elevated melatonin levels have been identified in the bone marrow of rats, with nighttime concentrations approximately twice as high as in the peripheral blood [41]. The enzymes involved in melatonin biosynthesis, N-acetyltransferase and hydroxyindole-o-methyltransferase are also expressed in bone marrow cells [17]. The presence of melatonin in bone marrow may be protective against oxidative damage in the proliferating hematopoietic cells or involved in bone development through osteoblast differentiation [42].

Several studies using various animal models show that melatonin prevents bone deterioration, including preventing idiopathic scoliosis in adolescents [40]. However, there was no correlation between gene variants and the phenotype for this particular disease [43]. Whether or not posture and gravity are determinants in these beneficial melatonin effects are still unclear. For example, pinealectomized Atlantic salmon show abnormal spinal curvature with a reduction in mechanical properties and vertebral mineral content reduction [39]. Pinealectomy in chickens induces histomorphometrical changes in the vertebral column. In particular, the loss of melatonin induces a scoliotic curvature and reduces mean weight and length of cervical vertebrae possibly due to a reduction in the total number of osteocytes. Melatonin, therefore, may act to enhance osteocyte proliferation in the cervical vertebrae [37]. In another study, it is shown that bipedal ambulation, in a mouse strain with genetically low levels of melatonin (C57BL/6J mice), induces scoliosis. Also, ambulation in C3H/HeJ mice, a mouse strain which displays normal melatonin rhythms, results in a scoliosis rate of 25% that increases to 70% when they are pinealectomized [44]. However, ambulation does not always induce scoliosis as demonstrated in rhesus monkeys. Here, it is found that pinealectomy in nonhuman primates does not produce idiopathic scoliosis [45].

The mechanism(s) by which melatonin protects bone may occur through its actions on both osteoclasts and osteoblasts and through an interaction with estrogen. As already known, the structural integrity of the skeletal system is dependent upon the continual remodeling process of bone-resorbing osteoclasts and bone-forming osteoblasts [46, 47]. Through this remodeling process, weakened bone is resorbed via activated osteoclasts and new bone is synthesized via activated osteoblasts. Melatonin may enhance bone formation by suppressing osteoclasts [48, 49] via its free radical scavenging properties and actions on RANKL and/or by enhancing osteoblast activity [42, 50] through specific melatonin receptors [40, 42].

Regarding its effects on osteoclasts, a study in goldfish scales indicates that melatonin enhances bone formation by inhibiting osteoclast activity. Tartrate-resistant acid phosphatase, a biomarker of osteoclast activity, significantly decreases after incubation with melatonin [48]. This study also shows that melatonin (1 nm) suppresses the activity of osteoblasts, possibly via a down-regulation of ER and insulin-like growth factor-1 mRNAs [48]. An interaction between melatonin and ERs is reported in other systems [8, 25] and is highlighted elsewhere in this review. The relationship between estrogen and melatonin is usually reciprocal in nature, however, in one study [51], melatonin actually enhanced its efficacy. Here, it is shown that melatonin administration (500 μg/day) prevents bone loss induced by ovariectomy in rats, but only if appropriate concentrations of estradiol are present. Also, in the study in question, melatonin enhanced the efficacy of estradiol in preventing bone loss [51].

Regarding the effect of melatonin on bone-forming osteoblasts, the data are conflicting. In the study using goldfish scales as their model, melatonin (1 nm) suppressed the activity of osteoblast cells [48]. Similar findings were also found in male Wistar rats whereby high endogenous levels of melatonin correlate with low levels of bone forming markers (i.e. alkaline phosphatase, carboxyterminal propeptide of type 1 procollagen, and carboxyterminal telopeptide of type 1 collagen) [28]. Also, pinealectomy results in induced levels of bone metabolism biomarkers and alters the phase and amplitude of their circadian oscillations [34].

By contrast, in other studies melatonin induced osteoblast activity either by enhancing their proliferation or differentiation. In preosteoblast MC3T3 cells, 50 nm melatonin stimulated bone mineralization and osteoblast differentiation, as assessed by bone marker proteins alkaline phosphatase, osteopontin and osteocalcin, via a transmembrane receptor that is pertusis toxin sensitive [50]. In human bone cells and human osteoblastic cells, melatonin increased the proliferation of both cell types in a dose-dependent manner [52] and, after a 2-day incubation, significantly increased the production of procollagen type I c-peptide. In human adult mesenchymal stem cells, melatonin (50 nm), acting through MT2 melatonin receptors, enhanced alkaline phosphatase activity by 50% relative to osteogenic media alone; this suggests that melatonin acts synergistically with the osteogenic medium to promote osteoblast development [42].

The signaling mechanisms underlying how melatonin enhances osteoblast cell formation are less well understood. In general, the promotion of osteoblast differentiation has been shown by numerous laboratories to be mediated via the mitogen activated protein kinase cascade [42, 53–57]; however, which ones (p38, MEK/ERK 1/2) remain unclear. The inputs leading to MAPK activation in osteoblastic cells may involve cAMP [57] and EGFR activation [42] (Fig. 1). Once activated, MAPK has been shown to phosphorylate osteoblast-specific proteins, including Cbfa-1 to control the expression of osteoblast-specific genes, including osteocalcin [56]. Clearly, the role of the MAPK pathway in melatonin-induced osteoblast differentiation is important and more studies are needed to further define these signaling cascades. In addition, the role of estrogen and melatonin in bone formation should be assessed as these combinational therapies may prove to be effective for the treatment of osteoporosis. Overall, the majority of the studies suggest a protective role of melatonin on bone, i.e. it prevents bone degradation and promotes bone formation most probably through an action that involves melatonin receptors. Furthermore, considering that bone-related genes are under a circadian rhythm [28, 34], determining the therapeutic window for melatonin's effects on bone marker proteins warrants further investigation as well.

Melatonin as a therapy for the prevention of cancer

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References

Decreased melatonin levels have been correlated with increased cancer risk, leading to suggestions of its potential as an antitumor or cancer preventative agent. The preponderance of the reports relate to melatonin's effects on breast cancer. Breast cancer risk is altered in instances that disrupt the normal cycling of melatonin levels, such as providing protection in blind women and an increased risk in women with reduced dark phases as a result of working in night shifts [58–61]. Studies in patients with breast cancer [62], lung cancer [63], and cervical cancer [64] have been found to have reduced nocturnal melatonin levels; whether these are a cause or consequence of the cancer is unknown. Disrupted circadian function in patients with advance non-small-cell lung cancer is also observed [65].

Melatonin is frequently concentrated in tissues, including the breast. Melatonin levels are higher in neoplastic breast tissues compared with serum levels, and higher concentrations are inversely correlated with nuclear grade or positively associated with ER status [66]. In clinical trials, on patients with different types of metastatic cancer, co-administration of melatonin and tamoxifen in untreatable metastatic cancer patients induced partial responses or stable disease in some patients and improved the survival time for some; this treatment also slowed cancer progression, and improved quality of life [67]. These data indicate that the anti-tumor properties of melatonin are relevant to cancer patients.

In a recent study that examined total melatonin produced over a 24-hr period, no correlation between melatonin levels and breast cancer was found [68]. However, from other studies it appears that the magnitude of the nocturnal rise in melatonin is more predictive of cancer risk rather than overall daily melatonin levels [10, 11, 69]. In studies examining nocturnal or first morning urine melatonin levels, an inverse correlation with breast cancer risk was noted [70]. Also, mutations in clock genes such as per-2 and per-3 results in an increase in spontaneous tumorigenesis in mice [71] or an increase in risk for premenopausal breast cancer [72], respectively.

Multiple mammary tumor studies on the effects of melatonin administration, constant light versus light/dark cycles, and pinealectomy to modify melatonin levels, demonstrate that melatonin has antitumor activities, including changes in cell proliferation, incidence of cancer, and latency to onset, in cultured cells and carcinogen-induced and spontaneous mammary cancer animal models [61, 62, 69, 73, 74]. Antimetastatic properties are also demonstrated using cultured MCF-7 cells [62]. Physiological levels of melatonin reduce the invasion of MCF-7 cells, and counteracts the increase in estrogen-induced invasiveness [75]. Melatonin also reduces the chemotactic response and increases the expression of cell surface adhesion molecules that have been inversely correlated with in vitro invasiveness [62]. Regarding telomerase activity, melatonin decreases its activity in the tumors of nude mice and the mRNA expression of the telomerase reverse transcriptase, the catalytic subunit of telomerase as well as the RNA telomerase subunit [76].

Mammary tumor studies in MMTV-neu mice with activated neu demonstrate that administration of melatonin during the darkness either with interrupted [77] or constant treatment [78] reduces the incidence of the primary and metastatic mammary tumors compared with untreated controls. In addition, the size of the mammary tumors are smaller after melatonin treatment suggesting an effect on tumor growth [77, 78]. Levels of neu expression in the tumors are also significantly decreased with melatonin treatment [77]. Higher doses of melatonin delay the onset, inhibit the growth, and reduce multiplicity and incidence of neu tumors [79].

Melatonin has multiple activities that could influence tumor initiation, promotion, and progression. The detoxifying properties of melatonin are potent, occur independent of its receptors and are protective against cancer [10–12]. The anti-proliferative and differentiating effects of melatonin may also occur through its receptors and thereafter through an inhibition of calmodulin [80] and/or a stimulation of [81] or inhibition of [61] the MEK/ERK 1/2 signaling cascades.

In humans, higher expression of MT1 receptors occur more frequently in breast tumors than normal breast epithelium and is associated with a high nuclear grade [82]. MT1 receptors are also expressed in tumors of the prostate [83]. Overexpression of MT1 receptors in MCF-7 cells renders the cells and xenografts more sensitive to melatonin therapy [84, 85]. Expression of MT1 receptors in S-91 murine melanoma cells (normally devoid of MT1 receptors), increases the anti-proliferative effects of melatonin [86]. Melatonin inhibits cell proliferation and transformation in MT1- or MT2-melatonin receptor expressing NIH 3T3 cells [87]. Also, in both rat hepatoma and human breast cancer xenografts, perfusion of these xenografts with melatonin-rich blood collected during the night from human subjects, significantly inhibits cAMP levels, MEK/ERK (1/2), linoleic acid uptake/metabolism and proliferative activity in these tumors. Additionally, these melatonin-induced effects are mediated by MT1/MT2 melatonin receptors as the addition of a nonselective melatonin receptor antagonist (S20928) blocks the effects [61]. Also, MT1 melatonin receptors, and MT3 receptors may be involved in the anti-proliferative effects of melatonin in human melanoma cells [88] and and MT2 melatonin receptors in the anti-proliferative effects of melatonin on an ER + human endometrial cancer cell line [89]. Also, the anti-proliferative effects of melatonin on tumor cells may be via its action on telomerase activity through melatonin receptors [76, 90].

Melatonin has additional activities that influence cancer, including modulation of the endocrine and immune systems [91] and stimulation of gap-junction intercellular communications [62, 73]. Reduced immune function resulting from lower melatonin levels may enhance tumor proliferation and reduce tumor surveillance [62]. Melatonin influences the levels of both estrogen and prolactin, which are also important in the promotion and proliferation of mammary tumors [25, 73]. In addition, melatonin downregulates ER levels in breast cancer cells and blocks ER DNA binding and transactivation functions [25, 77, 92–94]. Inhibition of estrogen results in the decrease in estrogen regulated factors such as cyclin D1 through its actions on c-jun and ATF-2, transcription factors known to bind to minimal estrogen-sensitive cyclin D1 promoter elements [95]. In addition, melatonin decreases EGF action via cross talk mechanisms with the ER [75]. Cumulatively, these data suggest melatonin should inhibit factors important in carcinogenesis and, thus, may have a role in cancer protection.

Melatonin as an adjuvant therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References

In numerous studies, the addition of melatonin with other treatments improves therapeutic outcomes because of its protective mechanisms and its ability to enhance the efficacy of these drugs [96, 97]. Clearly, melatonin enhances the actions of many different classes of drugs probably because of its diverse pharmacological actions at the cellular level. If the drug exhibits toxicity, as seen with many chemotherapeutic agents [98], then melatonin use as an adjuvant to current, clinically-accepted therapies may prove to be beneficial [99, 100]. Due to melatonin's ability to enhance the efficacy of some drugs, doses of these drugs could be adjusted to either reduce toxicities or enhance therapeutic effects. In addition, because of melatonin's ability to accumulate within a cell and function in detoxification, its use as an adjuvant is protective [99]. Furthermore, by virtue of its ability to activate multiple targets within the cell, melatonin may be useful in enhancing the therapeutic efficacy of other drugs class with similar functions. For example, melatonin, given in combination with tamoxifen, enhances the chemopreventative actions of tamoxifen by acting on a site other than the ER, e.g. calmodulin. In this scenario, tamoxifen acts to antagonize ERs in the breast whereas melatonin acts on calmodulin to inhibit ER binding to ERE-containing genes [25].

As melatonin is a chronobiotic agent and that many of its targets may exhibit circadian rhythms (Fig. 2), the timing of the administration to ensure maximum therapeutic efficacy may be a consideration. This idea is supported by recent findings showing that some tumors display circadian rhythms [29, 101, 102]. Many other genes also are rhythmic [11, 22, 23] (Fig. 2); however, whether they are targets for melatonin remain unanswered. Finally, the timing of melatonin could be used to reset circadian clocks in an attempt to reduce cancer risks associated with altered circadian rhythms [103].

In addition to its use as an adjuvant in treating cancer, the co-administration of melatonin with other therapies such as hormone replacement therapy (HRT) to decrease the risk factors associated with menopause, i.e. breast cancer, osteoporosis and stroke [8] should be considered. A negative correlation between the amplitude of the melatonin rhythm and circadian indicators of collagen metabolism exists [28, 34]. Therefore, a reduction in circulating melatonin levels may be a risk factor associated with the loss of bone in postmenopausal women. As reductions in melatonin occur during aging and also after HRT [104], restoring melatonin levels before the onset of menopause and maintaining this therapy during HRT, if needed, may help prevent bone loss and ultimately prevent osteoporosis.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References

In general, the mechanisms of action of melatonin remain poorly defined at the molecular level. Studies aimed to determine how melatonin produces its effects in its models should be determined so that proteins, other than melatonin receptors, can be targets for future drug development. Many current therapies for treating diseases such as cancer, osteoporosis and diabetes, use multiple drugs that act at different sites. This strategy is used to enhance the effectiveness of the therapy so as to improve the outcome of the treatment. Understanding whether the effects of melatonin in a given situation are being mediated via receptors or are receptor independent would aid in determining the efficacy of melatonin as a therapeutic agent. In addition, being that melatonin is a chronobiotic agent, and that many of its targets, including some tumors, contain clock genes [31] indicates that the timing of melatonin administration may determine its therapeutic efficacy (Fig. 2). As clock gene disruption increases spontaneous tumor formation in mice [71] and increases breast cancer risk in premenopausal women [72], then consideration should be given to those factors that desynchronize the internal timekeeping parameters to minimize these risks.

Although three areas were the focus of this review, this by no means negates or downplays the importance of melatonin use in other therapies, including its use as an anxiolytic or as an anti-hypertensive agent.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References

This review is dedicated to our dear friend, John S. Doctor, one of the authors of this review, who died suddenly. Even though he will be missed greatly, his memories will be cherished and his ideas put forward.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References
  • 1
    Touitou Y. Human aging and melatonin. Clinical relevance. Exp Gerontol 2001; 36:10831100.
  • 2
    Naji L, Carrillo-Vico A, Guerrero JM, Calvo JR. Expression of membrane and nuclear melatonin receptors in mouse peripheral organs. Life Sci 2004; 74:22272236.
  • 3
    Delagrange P, Atkinson J, Boutin JA et al. Therapeutic perspectives for melatonin agonists and antagonists. J Neuroendocrinol 2003; 15:442448.
  • 4
    Bubenik GA. Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci 2002; 47:23362348.
  • 5
    Carrillo-Vico A, Garcia-Perganeda A, Naji L, Calvo JR, Romero MP, Guerrero JM. Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system. Cell Mol Life Sci 2003; 60:22722278.
  • 6
    Karasek M. Melatonin, human aging, and age-related diseases. Exp Gerontol 2004; 39:17231729.
  • 7
    Chucharoen P, Chetsawang B, Srikiatkhachorn A, Govitrapong P. Melatonin receptor expression in rat cerebral artery. Neurosci Lett 2003; 341:259261.
  • 8
    Harrod CG, Bendok BR, Hunt Batjer H. Interactions between melatonin and estrogen may regulate cerebrovascular function in women: clinical implications for the effective use of HRT during menopause and aging. Med Hypotheses 2005; 64:725735.
  • 9
    Masana MI, Doolen S, Ersahin C et al. MT(2) melatonin receptors are present and functional in rat caudal artery. J Pharmacol Exp Ther 2002; 302:12951302.
  • 10
    Tomas-Zapico C, Coto-Montes A. A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes. J Pineal Res 2005; 39:99104.
  • 11
    Rodriguez C, Mayo JC, Sainz RM et al. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 2004; 36:19.
  • 12
    Vijayalaxmi, Reiter RJ, Tan DX, Herman TS, Thomas CR Jr. Melatonin as a radioprotective agent: a review. Int J Radiat Oncol Biol Phys 2004; 59:639653.
  • 13
    Zhao H, Poon AM, Pang SF. Pharmacological characterization, molecular subtyping, and autoradiographic localization of putative melatonin receptors in uterine endometrium of estrous rats. Life Sci 2000; 66:15811591.
  • 14
    Soares Jr JM, Masana MI, Ersahin C, Dubocovich ML. Functional melatonin receptors in rat ovaries at various stages of the estrous cycle. J Pharmacol Exp Ther 2003; 306:694702.
  • 15
    Clemens JW, Jarzynka MJ, Witt-Enderby PA. Down-regulation of mt1 melatonin receptors in rat ovary following estrogen exposure. Life Sci 2001; 69:2735.
  • 16
    Pintor J, Pelaez T, Hoyle CH, Peral A. Ocular hypotensive effects of melatonin receptor agonists in the rabbit: further evidence for an MT3 receptor. Br J Pharmacol 2003; 138:831836.
  • 17
    Cardinali DP, Ladizesky MG, Boggio V, Cutrera RA, Mautalen C. Melatonin effects on bone: experimental facts and clinical perspectives. J Pineal Res 2003; 34:8187.
  • 18
    Tsuchiya Y, Nishida E. Mammalian cultured cells as a model system of peripheral circadian clocks. J Biochem (Tokyo) 2003; 134:785790.
  • 19
    Reppert SM, Weaver DR, Ebisawa T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron 1994; 13:11771185.
  • 20
    Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci U S A 1995; 92:87348738.
  • 21
    Anisimov SV, Boheler KR, Anisimov VN. Microarray technology in studying the effect of melatonin on gene expression in the mouse heart. Dokl Biol Sci 2002; 383:9095.
  • 22
    Bailey MJ, Beremand PD, Hammer R, Bell-Pedersen D, Thomas TL, Cassone VM. Transcriptional profiling of the chick pineal gland, a photoreceptive circadian oscillator and pacemaker. Mol Endocrinol 2003; 17:20842095.
  • 23
    Bailey MJ, Beremand PD, Hammer R, Reidel E, Thomas TL, Cassone VM. Transcriptional profiling of circadian patterns of mRNA expression in the chick retina. J Biol Chem 2004; 279:5224752254.
  • 24
    Witt-Enderby PA, Bennett J, Jarzynka MJ, Firestine S, Melan MA. Melatonin receptors and their regulation: biochemical and structural mechanisms. Life Sci 2003; 72:21832198.
  • 25
    Sanchez-Barcelo EJ, Cos S, Mediavilla D, Martinez-Campa C, Gonzalez A, Alonso-Gonzalez C. Melatonin–estrogen interactions in breast cancer. J Pineal Res 2005; 38:217222.
  • 26
    Nosjean O, Ferro M, Coge F et al. Identification of the melatonin-binding site MT3 as the quinone reductase 2. J Biol Chem 2000; 275:3131131317.
  • 27
    Lewy AJ, Ahmed S, Jackson JM, Sack RL. Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol Int 1992; 9:380392.
  • 28
    Ostrowska Z, Kos-Kudla B, Marek B, Kajdaniuk D. Influence of lighting conditions on daily rhythm of bone metabolism in rats and possible involvement of melatonin and other hormones in this process. Endocr Regul 2003; 37:163174.
  • 29
    Blask DE, Sauer LA, Dauchy RT. Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem 2002; 2:113132.
  • 30
    Poirel VJ, Masson-Pevet M, Pevet P, Gauer F. MT1 melatonin receptor mRNA expression exhibits a circadian variation in the rat suprachiasmatic nuclei. Brain Res 2002; 946:6471.
  • 31
    Rutter J, Reick M, Mcknight SL. Metabolism and the control of circadian rhythms. Annu Rev Biochem 2002; 71:307331.
  • 32
    Magri F, Sarra S, Cinchetti W et al. Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians. J Pineal Res 2004; 36:256261.
  • 33
    Schmidt RE, Dorsey DA, Parvin CA, Beaudet LN. Sympathetic neuroaxonal dystrophy in the aged rat pineal gland. Neurobiol Aging 2005.
  • 34
    Ostrowska Z, Kos-Kudla B, Nowak M et al. The relationship between bone metabolism, melatonin and other hormones in sham-operated and pinealectomized rats. Endocr Regul 2003; 37:211224.
  • 35
    Abdel-Wanis ME, Kawahara N. Skeletal disorders associated with skin pigmentation: a role of melatonin? Med Hypotheses 2003; 61:640642.
  • 36
    Turgut M, Uslu S, Uysal A, Yurtseven ME, Ustun H. Changes in vascularity of cartilage endplate of degenerated intervertebral discs in response to melatonin administration in rats. Neurosurg Rev 2003; 26:133138.
  • 37
    Turgut M, Kaplan S, Turgut AT et al. Morphological, stereological and radiological changes in pinealectomized chicken cervical vertebrae. J Pineal Res 2005; 39:392399.
  • 38
    Inoh H, Kawakami N, Matsuyama Y et al. Correlation between the age of pinealectomy and the development of scoliosis in chickens. Spine 2001; 26:10141021.
  • 39
    Fjelldal PG, Grotmol S, Kryvi H et al. Pinealectomy induces malformation of the spine and reduces the mechanical strength of the vertebrae in Atlantic salmon, Salmo salar. J Pineal Res 2004; 36:132139.
  • 40
    Moreau A, Wang DAS, Forget S et al. Melatonin signaling dysfunction in adolescent idiopathic scoliosis. Spine 2004; 29:17721781.
  • 41
    Tan DX, Manchester LC, Reiter RJ et al. Identification of highly elevated levels of melatonin in bone marrow: its origin and significance. Biochim Biophys Acta 1999; 1472:206214.
  • 42
    Radio NM, Doctor JS, Witt-Enderby PA. Melatonin enhances alkaline phosphatase activity in differentiating human adult mesenchymal stem cells grown in osteogenic medium via MT2 melatonin receptors and the MEK/ERK (1/2) signaling cascade. J Pineal Res 2006; 40:332342.
  • 43
    Morcuende JA, Minhas R, Dolan L et al. Allelic variants of human melatonin 1A receptor in patients with familial adolescent idiopathic scoliosis. Spine 2003; 28:20252028; discussion 2029.
  • 44
    Oyama J, Murai I, Kanazawa K, Machida M. Bipedal ambulation induces experimental scoliosis in C57BL/6J mice with reduced plasma and pineal melatonin levels. J Pineal Res 2006; 40:219224.
  • 45
    Cheung KM, Wang T, Poon AM et al. The effect of pinealectomy on scoliosis development in young nonhuman primates. Spine 2005; 30:20092013.
  • 46
    Simmons DJ, Grynpass MD. Mechanisms of Bone Formation In vivo. The Telford Press, Caldwell, 1990.
  • 47
    Ducy P, Schinke T, Karsenty G. The osteoblast: a sophisticated fibroblast under central surveillance. Science 2000; 289:15011504.
  • 48
    Suzuki N, Hattori A. Melatonin suppresses osteoclastic and osteoblastic activities in the scales of goldfish. J Pineal Res 2002; 33:253258.
  • 49
    Koyama H, Nakade O, Takada Y, Kaku T, Lau KH. Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. J Bone Miner Res 2002; 17:12191229.
  • 50
    Roth JA, Kim BG, Lin WL, Cho MI. Melatonin promotes osteoblast differentiation and bone formation. J Biol Chem 1999; 274:2204122047.
  • 51
    Ladizesky MG, Boggio V, Albornoz LE, Castrillon PO, Mautalen C, Cardinali DP. Melatonin increases oestradiol-induced bone formation in ovariectomized rats. J Pineal Res 2003; 34:143151.
  • 52
    Nakade O, Koyama H, Ariji H, Yajima A, Kaku T. Melatonin stimulates proliferation and type I collagen synthesis in human bone cells in vitro. J Pineal Res 1999; 27:106110.
  • 53
    Suzuki A, Palmer G, Bonjour JP, Caverzasio J. Regulation of alkaline phosphatase activity by p38 MAP kinase in response to activation of Gi protein-coupled receptors by epinephrine in osteoblast-like cells. Endocrinology 1999; 140:31773182.
  • 54
    Suzuki A, Guicheux J, Palmer G et al. Evidence for a role of p38 MAP kinase in expression of alkaline phosphatase during osteoblastic cell differentiation. Bone 2002; 30:9198.
  • 55
    Rawadi G, Ferrer C, Spinella-Jaegle S, Roman-Roman S, Bouali Y, Baron R. 1-(5-oxohexyl)-3,7-Dimethylxanthine, a phosphodiesterase inhibitor, activates MAPK cascades and promotes osteoblast differentiation by a mechanism independent of PKA activation (pentoxifylline promotes osteoblast differentiation). Endocrinology 2001; 142:46734682.
  • 56
    Xiao G, Jiang D, Thomas P et al. MAPK pathways activate and phosphorylate the osteoblast-specific transcription factor, Cbfa1. J Biol Chem 2000; 275:44534459.
  • 57
    Fujita T, Meguro T, Fukuyama R, Nakamuta H, Koida M. New signaling pathway for parathyroid hormone and cyclic AMP action on extracellular-regulated kinase and cell proliferation in bone cells. Checkpoint of modulation by cyclic AMP. J Biol Chem 2002; 277:2219122200.
  • 58
    Rohr UD, Herold J. Melatonin deficiencies in women. Maturitas 2002; 41(Suppl. 1): S85S104.
  • 59
    Schernhammer ES, Laden F, Speizer FE et al. Rotating night shifts and risk of breast cancer in women participating in the nurses’ health study. J Natl Cancer Inst 2001; 93:15631568.
  • 60
    Megdal SP, Kroenke CH, Laden F, Pukkala E, Schernhammer ES. Night work and breast cancer risk: a systematic review and meta-analysis. Eur J Cancer 2005; 41:20232032.
  • 61
    Blask DE, Brainard GC, Dauchy RT et al. Melatonin-depleted blood from premenopausal women exposed to light at night stimulates growth of human breast cancer xenografts in nude rats. Cancer Res 2005; 65:1117411184.
  • 62
    Cos S, Sanchez-Barcelo EJ. Melatonin and mammary pathological growth. Front Neuroendocrinol 2000; 21:133170.
  • 63
    Mazzoccoli G, Carughi S, De Cata A, La Viola M, Vendemiale G. Melatonin and cortisol serum levels in lung cancer patients at different stages of disease. Med Sci Monit 2005; 11:CR284288.
  • 64
    Karasek M, Kowalski AJ, Suzin J, Zylinska K, Swietoslawski J. Serum melatonin circadian profiles in women suffering from cervical cancer. J Pineal Res 2005; 39:7376.
  • 65
    Levin RD, Daehler MA, Grutsch JF et al. Circadian function in patients with advanced non-small-cell lung cancer. Br J Cancer 2005; 93:12021208.
  • 66
    Maestroni GJ, Conti A. Melatonin in human breast cancer tissue: association with nuclear grade and estrogen receptor status. Lab Invest 1996; 75:557561.
  • 67
    Lissoni P, Paolorossi F, Tancini G et al. A phase II study of tamoxifen plus melatonin in metastatic solid tumour patients. Br J Cancer 1996; 74:14661468.
  • 68
    Travis RC, Allen DS, Fentiman IS, Key TJ. Melatonin and breast cancer: a prospective study. J Natl Cancer Inst 2004; 96:475482.
  • 69
    Vijayalaxmi, Thomas CR Jr, Reiter RJ, Herman TS. Melatonin: from basic research to cancer treatment clinics. J Clin Oncol 2002; 20:25752601.
  • 70
    Schernhammer ES, Hankinson SE. Urinary melatonin levels and breast cancer risk. J Natl Cancer Inst 2005; 97:10841087.
  • 71
    Canaple L, Kakizawa T, Laudet V. The days and nights of cancer cells. Cancer Res 2003; 63:75457552.
  • 72
    Zhu Y, Brown HN, Zhang Y, Stevens RG, Zheng T. Period3 structural variation: a circadian biomarker associated with breast cancer in young women. Cancer Epidemiol Biomarkers Prev 2005; 14:268270.
  • 73
    Cos S, Sanchez-Barcelo EJ. Melatonin, experimental basis for a possible application in breast cancer prevention and treatment. Histol Histopathol 2000; 15:637647.
  • 74
    Lenoir V, De Jonage-Canonico MB, Perrin MH, Martin A, Scholler R, Kerdelhue B. Preventive and curative effect of melatonin on mammary carcinogenesis induced by dimethylbenz[a]anthracene in the female Sprague–Dawley rat. Breast Cancer Res 2005; 7:R470R476.
  • 75
    Cos S, Blask DE. Melatonin modulates growth factor activity in MCF-7 human breast cancer cells. J Pineal Res 1994; 17:2532.
  • 76
    Leon-Blanco MM, Guerrero JM, Reiter RJ, Calvo JR, Pozo D. Melatonin inhibits telomerase activity in the MCF-7 tumor cell line both in vivo and in vitro. J Pineal Res 2003; 35:204211.
  • 77
    Baturin DA, Alimova IN, Anisimov VN et al. The effect of light regimen and melatonin on the development of spontaneous mammary tumors in HER-2/neu transgenic mice is related to a downregulation of HER-2/neu gene expression. Neuro Endocrinol Lett 2001; 22:441447.
  • 78
    Anisimov VN, Alimova IN, Baturin DA et al. The effect of melatonin treatment regimen on mammary adenocarcinoma development in HER-2/neu transgenic mice. Int J Cancer 2003; 103:300305.
  • 79
    Rao GN, Ney E, Herbert RA. Effect of melatonin and linolenic acid on mammary cancer in transgenic mice with c-neu breast cancer oncogene. Breast Cancer Res Treat 2000; 64:287296.
  • 80
    Dai J, Inscho EW, Yuan L, Hill SM. Modulation of intracellular calcium and calmodulin by melatonin in MCF-7 human breast cancer cells. J Pineal Res 2002; 32:112119.
  • 81
    Bordt SL, Mckeon RM, Li PK, Witt-Enderby PA, Melan MA. N1E-115 mouse neuroblastoma cells express MT1 melatonin receptors and produce neurites in response to melatonin. Biochim Biophys Acta 2001; 1499:257264.
  • 82
    Dillon DC, Easley SE, Asch BB et al. Differential expression of high-affinity melatonin receptors (MT1) in normal and malignant human breast tissue. Am J Clin Pathol 2002; 118:451458.
  • 83
    Shiu SY, Law IC, Lau KW, Tam PC, Yip AW, Ng WT. Melatonin slowed the early biochemical progression of hormone-refractory prostate cancer in a patient whose prostate tumor tissue expressed MT1 receptor subtype. J Pineal Res 2003; 35:177182.
  • 84
    Yuan L, Collins AR, Dai J, Dubocovich ML, Hill SM. MT(1) melatonin receptor overexpression enhances the growth suppressive effect of melatonin in human breast cancer cells. Mol Cell Endocrinol 2002; 192:147156.
  • 85
    Collins A, Yuan L, Kiefer TL, Cheng Q, Lai L, Hill SM. Overexpression of the MT1 melatonin receptor in MCF-7 human breast cancer cells inhibits mammary tumor formation in nude mice. Cancer Lett 2003; 189:4957.
  • 86
    Kadekaro AL, Andrade LN, Floeter-Winter LM et al. MT-1 melatonin receptor expression increases the antiproliferative effect of melatonin on S-91 murine melanoma cells. J Pineal Res 2004; 36:204211.
  • 87
    Jones MP, Melan MA, Witt-Enderby PA. Melatonin decreases cell proliferation and transformation in a melatonin receptor-dependent manner. Cancer Lett 2000; 151:133143.
  • 88
    Vieira De Souza A, Visconti MA, De Lauro Castrucci AM. Melatonin biological activity and binding sites in human melanoma cells. J Pineal Res 2003; 34:242248.
  • 89
    Kobayashi Y, Itoh MT, Kondo H et al. Melatonin binding sites in estrogen receptor-positive cells derived from human endometrial cancer. J Pineal Res 2003; 35:7174.
  • 90
    Leon-Blanco MM, Guerrero JM, Reiter RJ, Pozo D. RNA expression of human telomerase subunits TR and TERT is differentially affected by melatonin receptor agonists in the MCF-7 tumor cell line. Cancer Lett 2004; 216:7380.
  • 91
    Carrillo-Vico A, Garcia-Maurino S, Calvo JR, Guerrero JM. Melatonin counteracts the inhibitory effect of PGE2 on IL-2 production in human lymphocytes via its mt1 membrane receptor. FASEB J 2003; 17:755757.
  • 92
    Rato AG, Pedrero JG, Martinez MA, Del Rio B, Lazo PS, Ramos S. Melatonin blocks the activation of estrogen receptor for DNA binding. FASEB J 1999; 13:857868.
  • 93
    Kiefer T, Ram PT, Yuan L, Hill SM. Melatonin inhibits estrogen receptor transactivation and cAMP levels in breast cancer cells. Breast Cancer Res Treat 2002; 71:3745.
  • 94
    Del Rio B, Garcia Pedrero JM, Martinez-Campa C, Zuazua P, Lazo PS, Ramos S. Melatonin, an endogenous-specific inhibitor of estrogen receptor alpha via calmodulin. J Biol Chem 2004; 279:3829438302.
  • 95
    Cini G, Neri B, Pacini A et al. Antiproliferative activity of melatonin by transcriptional inhibition of cyclin D1 expression: a molecular basis for melatonin-induced oncostatic effects. J Pineal Res 2005; 39:1220.
  • 96
    Lissoni P, Chilelli M, Villa S, Cerizza L, Tancini G. Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial. J Pineal Res 2003; 35:1215.
  • 97
    Mills E, Wu P, Seely D, Guyatt G. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res 2005; 39:360366.
  • 98
    Reiter RJ, Tan DX, Sainz RM, Mayo JC, Lopez-Burillo S. Melatonin: reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmacol 2002; 54:12991321.
  • 99
    Yavuz MN, Yavuz AA, Ulku C et al. Protective effect of melatonin against fractionated irradiation-induced epiphyseal injury in a weanling rat model. J Pineal Res 2003; 35:288294.
  • 100
    Anwar MM, Mahfouz HA, Sayed AS. Potential protective effects of melatonin on bone marrow of rats exposed to cytotoxic drugs. Comp Biochem Physiol A Mol Integr Physiol 1998; 119:493501.
  • 101
    Bartsch H, Bartsch C, Deerberg F, Mecke D. Seasonal rhythms of 6-sulphatoxymelatonin (aMT6s) excretion in female rats are abolished by growth of malignant tumors. J Pineal Res 2001; 31:5761.
  • 102
    You S, Wood PA, Xiong Y, Kobayashi M, Du-Quiton J, Hrushesky WJ. Daily coordination of cancer growth and circadian clock gene expression. Breast Cancer Res Treat 2005; 91:4760.
  • 103
    Mahmoud F, Sarhill N, Mazurczak MA. The therapeutic application of melatonin in supportive care and palliative medicine. Am J Hosp Palliat Care 2005; 22:295309.
  • 104
    Kos-Kudla B, Ostrowska Z, Marek B et al. Circadian rhythm of melatonin in postmenopausal asthmatic women with hormone replacement therapy. Neuro Endocrinol Lett 2002; 23:243248.