• androgen;
  • chemoprevention;
  • melatonin;
  • MT1 receptor;
  • p27Kip1;
  • prostate cancer;
  • prostate-specific antigen


  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence in support of the melatonin hypothesis in prostate cancer
  5. Melatonin signalling in antiproliferation of prostate cancer versus breast cancer epithelial cells
  6. Prostate cancer prevention: role of melatonin
  7. Prostate cancer treatment: role of melatonin
  8. Conclusions
  9. Acknowledgements
  10. References

Abstract:  Prostate cancer is a public health problem of the elderly men. It has been estimated that one in six men will develop prostate cancer in his lifetime in the USA. There is thus a huge clinical demand for effective therapies for the prevention and treatment of the disease. Here, the scientific evidence supporting the effectiveness of melatonin in inhibiting the development and progression of prostate cancer is reviewed. The rational use of melatonin in prostate cancer prevention, stabilization of clinically localized favourable-risk prostate cancer and palliative treatment of advanced or metastatic tumour is discussed within the context of the molecular pathogenesis of the disease.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence in support of the melatonin hypothesis in prostate cancer
  5. Melatonin signalling in antiproliferation of prostate cancer versus breast cancer epithelial cells
  6. Prostate cancer prevention: role of melatonin
  7. Prostate cancer treatment: role of melatonin
  8. Conclusions
  9. Acknowledgements
  10. References

In the past 50 yrs, there have been significant changes in the spectrum of diseases threatening human survival in the western world. Extension of the average human life expectancy as a result of advances in medical science and technology is paralleled by increases in cancer incidence, morbidity and mortality in developed countries. Cancer is now the second most common cause of death in the USA and accounts for one of every four deaths [1]. This group of diseases creates an ever-escalating demand for safer and better medications and therapies for cancer prevention and treatment. To meet this challenging demand, the entire scientific research enterprise has, over the years, identified, synthesized and tested many promising anticancer agents, which target-specific signalling pathways involved in the development and progression of different types of cancer. Among these agents, melatonin, a circadian and circannual time signal secreted by the human pineal gland [2–4], has emerged to be a nutraceutical as well as a safe pharmaceutical with significant anticancer potentials [5–8].

Ever since the melatonin hypothesis was formulated which suggested a link between the pineal melatonin and breast cancer development [9], the majority of cancer research on melatonin in the past three decades has centred largely on the growth-inhibitory effects of the pineal indoleamine on breast cancer [10–14], which is the most common female cancer [1]. In contrast, despite the fact that human prostate cancer is the most commonly diagnosed noncutaneous cancer in the males [1], research efforts on melatonin in prostate cancer have received less attention.

In this review, important scientific evidence in support of the melatonin hypothesis in prostate cancer development and our current understanding of the major signalling mechanisms of melatonin in growth regulation of prostate cancer cell versus breast cancer cell are summarized. Furthermore, practical strategies to move melatonin effectively from the laboratory into the clinic for prostate cancer prevention and treatment are discussed, with reference to the recent scientific advances in the molecular pathogenesis and clinical management of the disease.

Evidence in support of the melatonin hypothesis in prostate cancer

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence in support of the melatonin hypothesis in prostate cancer
  5. Melatonin signalling in antiproliferation of prostate cancer versus breast cancer epithelial cells
  6. Prostate cancer prevention: role of melatonin
  7. Prostate cancer treatment: role of melatonin
  8. Conclusions
  9. Acknowledgements
  10. References

As in breast cancer, an inverse relationship between melatonin production and human prostate cancer incidence has been shown by epidemiological and clinical studies, which support a potential prostate tumour suppressive function of melatonin. Of note, winter darkness and visual impairment appear to protect, respectively, indigenous Nordic people and the blind from prostate cancer [15–18]. It is well known that human melatonin production decreases with age [19–22], and this is associated with increases in prostate cancer incidence with advancing age in elderly men. Moreover, melatonin levels are lower in prostate cancer patients than in patients suffering from benign prostatic hyperplasia (BPH) [23].

Importantly, the above-mentioned circumstantial epidemiological and clinical evidence is strongly corroborated by recent laboratory data. Independently, we [24–26] and others [27–30] have reported growth-inhibitory actions of melatonin on human prostate cancer cells in culture and in nude mice. While two reports suggested that the observed antiproliferative actions of melatonin might be mediated by membrane receptor-independent mechanisms, our group has consistently demonstrated an association between melatonin antiproliferation and MT1 receptor expression in androgen-independent human prostate cancer cells in culture [24] and in tissue xenografts in both intact and castrated nude mice [25, 26]. Furthermore, administration of melatonin to a castrated prostate cancer patient whose prostate tumour tissue expressed MT1 receptor was found to slow the early biochemical progression, as indicated by serum prostate-specific antigen (PSA) level changes, of his hormone-refractory tumour [31]. This proof-of-concept translational study in a human subject provided strong support for the MT1 receptor playing a key role in mediating the direct antiproliferative prostate tumour-suppressive action of melatonin. Indeed, we have most recently shown that the antiproliferative effect of melatonin on androgen-independent prostate cancer cells was blocked by luzindole, a nonselective MT1 and MT2 receptor antagonist, but was unaffected by 4-phenyl-2-propionamidotetraline (4-P-PDOT), a selective MT2 receptor antagonist [32].

Melatonin signalling in antiproliferation of prostate cancer versus breast cancer epithelial cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence in support of the melatonin hypothesis in prostate cancer
  5. Melatonin signalling in antiproliferation of prostate cancer versus breast cancer epithelial cells
  6. Prostate cancer prevention: role of melatonin
  7. Prostate cancer treatment: role of melatonin
  8. Conclusions
  9. Acknowledgements
  10. References

The discoveries of specific G-protein-coupled melatonin receptor subtypes [33], and receptor-dependent as well as receptor-independent antioxidant actions of melatonin [34, 35] have accelerated research into the signal transduction mechanisms of melatonin in cancer cell biology. Collectively, all the evidence indicates that the most common anticancer action of melatonin is antiproliferation. This can be mediated by receptor-dependent and/or receptor-independent mechanisms. Depending on the tissue origins of different types of cancer, one of these mechanisms may play a dominant role in melatonin-induced antiproliferation. For example, the oncostatic action of melatonin is largely mediated by MT1 receptor in melanoma [36], hepatoma [37–40] and breast cancer cells [41–43], whereas the antioxidant action of melatonin plays a more important role in glioma antiproliferation [44]. So far, mapping of the signal transduction pathways of melatonin in growth modulation of breast cancer epithelial cells has been more advanced than those of other tumours, and some intracellular signalling steps that are activated by melatonin in hepatoma may also be responsible for the transmission of melatonin antiproliferation signal in breast cancer [43]. Hence, in breast cancer cell, it has been proposed that a major mechanism by which melatonin exerts its antiproliferative effect is via MT1 receptor-mediated inhibition of cAMP ([DOWNWARDS ARROW]cAMP) with resultant blockade of tumour linoleic acid (LA) uptake and its conversion, by 15-lipoxygenase-1 enzyme, to 13-hydroxyoctadecadienoic acid (13-HODE), which normally activates EGFR/MEK/ERK1/2 mitogenic signalling [43]. Taking into account the research findings on interactions between melatonin and mitogenic oestrogen signalling in growth regulation of breast cancer cells [45, 46], apparently, through downregulation of ERK1/2 signalling, melatonin can decrease the expression of oestrogen receptor (ERα) in breast cancer cells [43], and together with MT1 receptor/[DOWNWARDS ARROW]cAMP-mediated inhibition of E2–ERα complex binding to the oestrogen response element (ERE) of responsive proliferation-associated genes, melatonin can effectively inhibit oestrogen (E2) mitogenic signalling [45, 46].

Similarly, melatonin signalling research in prostate cancer has largely focused on the direct antiproliferative action of melatonin and its interaction with mitogenic androgenic signalling. Our current understanding of the major signal transduction mechanisms of melatonin in the modulation of prostate cancer epithelial cell proliferation is illustrated in Fig. 1. Most importantly, melatonin activates the MT1 receptor to inhibit the proliferation of hormone-refractory prostate cancer 22Rv1 cells by upregulating p27Kip1 gene and protein expression through a novel signalling mechanism involving coactivation of protein kinase C (PKC) and protein kinase A (PKA) in parallel [32]. Of note, the cyclin-dependent kinase (cdk) inhibitor p27Kip1 is a well-known tumour suppressor protein which functions as a mitotic inhibitor in cell cycle progression [47]. This is, so far, the strongest evidence in the literature demonstrating a more direct mechanistic link between melatonin and the expression of critical cell cycle control proteins implicated in human carcinogenesis. Though melatonin has also been reported to induce changes in other important cell cycle regulatory proteins such as p53, p21cip1/Waf1 and cyclin D1 in breast cancer cells [48, 49], the molecular mechanisms involved have not yet been defined in comparable details.


Figure 1.  Schematic diagram showing the signalling pathways implicated in melatonin-induced antiproliferation of prostate cancer cells and its relations to DHT/AR, PTEN and p27Kip1 signalling. [RIGHTWARDS ARROW] denotes activation; ⊣ denotes inhibition. PKC, protein kinase C; PKA, protein kinase A; DHT, dihydrotestosterone; AR, androgen receptor; PSA, prostate-specific antigen; GF, growth factor; GFR, growth factor receptor; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-diphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, phosphatase and tensin homologue; AKT, protein kinase B.

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Whereas in breast cancer, melatonin induces antiproliferation mainly through downregulation of mitogenic ERK1/2 signalling via melatonin/MT1/[DOWNWARDS ARROW]cAMP/[DOWNWARDS ARROW]LA uptake/[DOWNWARDS ARROW]15-LOX-1/[DOWNWARDS ARROW]13-HODE signal transduction pathway [43], effective antiproliferation in prostate cancer can apparently be induced via melatonin/MT1/PKA + PKC/p27Kip1 [32]. The melatonin/MT1/PKA + PKC/p27Kip1 signalling pathway that has been characterized in prostate cancer, appears to act independently, as illustrated in Fig. 1, from the activated phosphoinositide 3-kinase (PI3K)/AKT (protein kinase B) growth-promoting signalling [32]. Activation of PI3K/AKT signalling, as a consequence of mutational loss of phosphatase and tensin homologue (PTEN) functions, has been shown to contribute significantly to the downregulated p27Kip1 expression observed in human prostate cancer progression, through inhibition of p27Kip1 promoter transactivation by the FOXO transcription factors [50–52]. As in breast cancer, crosstalks between melatonin and sex steroid (androgenic) signalling have been demonstrated in prostate cancer. PKC-induced downregulation of androgen-induced transcriptional activity of androgen receptor (AR) [32, 53], and melatonin-induced nuclear exclusion of AR via PKC activation have been reported in prostate cancer epithelial cells [54–56]. Interestingly, unlike the effects of melatonin in breast cancer cells, the indole does not reduce AR binding to the androgen responsive element (ARE) in the promoter of androgen-responsive genes, and does not decrease AR level in prostate cancer cells [53, 57]. It can be inferred that melatonin/MT1/PKC activation can downregulate activated androgenic signalling by decreasing AR-mediated transcriptional activity through nuclear exclusion of AR. Clearly, melatonin antiproliferative signalling in prostate cancer is distinctively different from that in breast cancer.

Prostate cancer prevention: role of melatonin

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence in support of the melatonin hypothesis in prostate cancer
  5. Melatonin signalling in antiproliferation of prostate cancer versus breast cancer epithelial cells
  6. Prostate cancer prevention: role of melatonin
  7. Prostate cancer treatment: role of melatonin
  8. Conclusions
  9. Acknowledgements
  10. References

Prostate cancer is an attractive disease for primary prevention because of its incidence, prevalence and disease-related mortality. It is believed that interruption of the biological process involved in carcinogenesis will inhibit this process and, in turn, reduce cancer incidence. Carcinogenesis of the prostate epithelial cell occurs slowly over a protracted period with accumulation of a series of genetic and epigenetic changes in important cellular oncogenes and tumour suppressor genes, leading to uncontrolled cell proliferation [58].

Advancing age is the most established risk factor for prostate cancer. Approximately 75% of new prostate cancer patients are older than 65 yr of age. Whereas increased risks are found in relatives of prostate cancer patients and there is a strong association of developing prostate cancer between monozygotic twins, no single gene or chromosomal region has, so far, been implicated in prostate cancer development, despite some hot-spots in the genome have been identified [59, 60]. Based on our current understanding of the molecular and cellular changes involved in the development and progression of prostate cancer, the evolution of the disease over time is depicted schematically in Fig. 2A. Of note, clinically evident prostate cancer is rare in men under 50 yr of age, while the precancerous prostatic intraepithelial neoplasia (PIN) [61] is found in men as early as in their 30s and 40s [62, 63]. To date, identification of key molecular alterations in prostate cancer cells implicates AR-mediated growth-stimulatory signalling pathways, carcinogen defences (glutathione S-transferase π, also known as GSTP1), and growth-inhibitory signalling pathways (PTEN and p27Kip1), as the critical determinants of the phenotype of prostate cancer cells. These molecular changes help us define specific targets for the prevention and treatment of prostate cancer [64].


Figure 2.  Timeline of development/progression of prostate cancer with important molecular markers of pathogenesis (A), and castration-induced emergence of androgen-independent tumour (B).

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Androgens are of primary importance in the aetiology of prostate cancer, and prostate cells, along with prostate cancer cells, require the presence of androgens to survive. Historically, Charles Huggins showed, in 1940, that testosterone removal (castration) resulted in rapid shrinkage of the enlarged prostate of older dogs, the only nonprimate animals that develop prostate cancer. In 1941, Charles Huggins and Clarence Hodges demonstrated that patients with advanced prostate cancer responded to androgen removal. Since then, the contribution of AR-signalling axis to many aspects of prostate cancer, including initiation, progression and resistance to current forms of therapy has been increasingly recognized [65].

Castration or androgen deprivation therapy (ADT) is still the recommended palliative treatment for advanced or metastatic prostate cancer today. Indeed, the relevance of androgenic mitogenic signalling in prostate carcinogenesis is strongly documented recently by the report on the overexpression of oncogenic ETS transcription factors driven by the fused androgen-responsive promoter elements of the TMPRSS2 gene, as a result of chromosomal translocations in primary prostate cancer and PIN lesions [66–68]. As a result of the crucial role of androgens in prostate carcinogenesis, hormonal agents, such as 5α-reductase inhibitors, are among the first candidate agents to be tested for primary chemoprevention of prostate cancer. The Prostate Cancer Prevention Trial (PCPT) has demonstrated that finasteride, a type 2-specific 5α-reductase inhibitor, can prevent prostate cancer, albeit with an apparently increased risk of high-grade disease [69]. However, doctors are reluctant to recommend finasteride because of the reported increased incidence of high-grade prostate cancer associated with its administration in the preventive setting. Moreover, the attractiveness of finasteride is also compromised by the occurrence of sex-related adverse events and the high cost of this drug.

Currently, the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial is under way, assessing dutasteride, a dual inhibitor of type 1 and type 2 5α-reductase inhibitor, to see if it would be a better drug than finasteride for prostate cancer primary chemoprevention. Given that dutasteride therapy reduces serum DHT significantly more than finasteride does in men with BPH [70] and that there might be increased expression of type 1 5α-reductase in prostate cancer versus benign prostatic tissue [71], dutasteride may prove to be more potent than finasteride in prostate cancer prevention. Nonetheless, there does not appear to be any clinically significant difference between the adverse event profiles of dutasteride and finasteride [70], and similar concerns for finasteride may limit the future use of dutasteride in prostate cancer prevention.

Based on the natural history of prostate cancer evolution (Fig. 2A), the period before PIN development and the time interval when preneoplastic PIN lesions progress to latent prostate cancer (i.e. when the age of the individual men is between 30s and 50s) may be the therapeutic time windows for effective primary prevention. The rationale behind one of the preventive approaches may be connected with our current understanding of the role of GSTP1, the gene encoding the π-class glutathione S-transferase (GST), in prostate carcinogenesis. GSTP1 has been proposed to serve a ‘caretaker’ function for prostatic cells. Although GSTP1 can be detected in normal prostatic epithelium, prostate cancer cells fail to express GSTP1 polypeptides as a result of somatic ‘CpG island’ DNA methylation changes. Loss of GSTP1 function also appears to be characteristic of PIN lesions. It has been suggested that prostate epithelial cells with defective GSTP1 will become vulnerable to endogenous reactive oxygen species that inflict genomic damage which will promote transformation to PIN cells. Subsequently, PIN cells with defective GSTPI genes remain vulnerable to similar oxidant stresses which further promote malignant progression to prostate cancer [72]. Thus, a logical way to prevent the formation and/or progression of PIN to prostate cancer is to abrogate genotoxic stresses via avoidance of exogenous carcinogens and/or reduction of endogenous carcinogenic oxidant stresses. Together with a substantial amount of epidemiological, molecular and clinical evidence which suggests that antioxidants such as selenium and vitamin E might prevent prostate cancer, this combination is, indeed, being tested for prostate cancer prevention in the ongoing Selenium and Vitamin E Cancer Prevention Trial (SELECT).

Although selenium and vitamin E are common nutraceuticals, it is important to note that a recent meta-analysis of vitamin E trials has concluded that higher doses (≥400 IU/day) of vitamin E supplements may increase all-cause mortality and should be avoided [73]. While the results of the SELECT trial are eagerly awaited, it remains to be seen whether or not this potential adverse effect of vitamin E at high dosages will compromise future use of vitamin E (given as 400 IU/day in the SELECT trial) with or without selenium in prostate cancer prevention.

Recent dissection of the molecular signalling events involved in prostate cancer development in genetically modified mouse models of cancer has implicated the crucial role of the tumour suppressor PTEN, particularly, in prostate carcinogenesis. The PTEN gene is mutated in a variety of human cancer at a frequency equal to that of p53 [74]. PTEN is a negative regulator of the PI3K/AKT pathway, which is frequently activated in many different types of malignancies. Previously, it has been reported that about 70% of primary prostate cancer show loss of at least one allele of PTEN, whereas homozygous inactivation of PTEN is generally associated with advanced cancer and metastases [75]. Loss of PTEN in vivo results in activation of the AKT pathway and susceptibility to tumorigenesis, which is closely related to the degree of PTEN insufficiency [76–78]. Whereas loss of one allele of PTEN is associated with the development of (high-grade) PIN, complete loss of PTEN in the prostate triggers a p53 cellular senescence response, thereby limiting progression of PIN lesions in vivo. As a result, bypass of p53-mediated senescence will be critical for the development of cancer from PIN lesions [79].

Moreover, it is well known that there is an inverse correlation between p27Kip1 expression and prognosis in various human tumours, including prostate cancer [47], and decrease in p27Kip1 expression has been consistently reported in PIN lesions [80, 81]. Loss of PTEN has also been shown to cooperate with the loss of other tumour suppressors frequently found inactivated in prostate cancer (p53 and p27Kip1) to accelerate carcinogenesis [82, 83]. Collectively, the above evidence indicates that specific molecularly targeted therapies developed against the tumour suppressor PTEN, p27Kip1 and p53 signalling pathways, alone or in combination, will be most effective for prostate cancer prevention. Considering that increased PI3K/AKT signalling with mutated PTEN functions contributes significantly, as described above, to the downregulated expression of p27Kip1 observed in human prostate cancer progression [50–52], and that melatonin can act through MT1/PKA + PKC signalling pathway to upregulate p27Kip1 gene expression in prostate cancer cell [32], the pineal indoleamine, by inference, would be able to abrogate the downregulated p27Kip1 expression due to loss of PTEN functions. Thus, by targeting p27Kip1 signalling and being itself also a nutraceutical with antioxidant properties [34], melatonin would be an ideal candidate molecule to be tested for prostate cancer primary prevention.

Prostate cancer treatment: role of melatonin

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence in support of the melatonin hypothesis in prostate cancer
  5. Melatonin signalling in antiproliferation of prostate cancer versus breast cancer epithelial cells
  6. Prostate cancer prevention: role of melatonin
  7. Prostate cancer treatment: role of melatonin
  8. Conclusions
  9. Acknowledgements
  10. References

Treatment options for prostate cancer vary according to patients’ age and the stage of cancer [84]. Currently, there are three treatment options for clinically localized disease: curative radical prostatectomy, curative radical radiotherapy and watchful waiting with active surveillance by serial PSA monitoring and periodic prostate biopsies [85]. While improvements in screening and diagnosis have led to significant reduction in mortality, PSA-based prostate cancer screening results in the diagnosis in many men whose tumour are not destined to have clinical progression during their lifetime [86]. The curative prospects of radical interventions in clinically localized prostate cancer have to be weighed against well-documented side effects of radical prostatectomy and radiotherapy such as erectile dysfunction, incontinence and long-term bowel problems such as diarrhoea. Although patients under watchful waiting may have the advantages of avoiding the above potential risks of surgery and radiotherapy and they may still have similar overall survival and quality of life to that enjoyed by men treated with radical interventions, patients under active surveillance would have to bear the anxiety associated with the risk of disease progression which may lead to premature death.

So far, there is no good evidence that any of these treatment options is superior in terms of improving survival. As a result, treating men with clinically localized prostate cancer is extremely controversial, and further optimization of the treatment methods to the biology of the tumour is necessary. In this era of prostate cancer screening, about half (50%) of the newly diagnosed prostate cancer are of the favourable-risk prostate cancer type, defined as a histopathological Gleason score of 6 or less, serum PSA < 10 ng/mL, and a clinical stage of T1c to T2a. In most of these patients, the disease is indolent and slow growing.

The challenge is to identify those patients who are unlikely to experience significant progression, while offering radical therapy to those who are at risk. To meet this challenge, a rational approach of active surveillance with selective delayed radical intervention based on PSA doubling time (PSADT, which reflects biochemical progression) and repeat biopsy (which shows tissue grade progression) has been formulated to represent a practical compromise between radical therapy for all (which results in overtreatment for patients with indolent disease) and watchful waiting with supportive treatment only (which results in undertreatment for those with aggressive disease) [87, 88].

Given that melatonin can slow the biochemical progression of prostate cancer (as indicated by a decline in the PSADT) in a human subject [31], the use of melatonin may further reduce the risk of cancer progression by disease stabilization and thereby allay the attendant anxiety in this subgroup of patients having clinically localized disease with favourable outcome, which could have been identified by this rational approach of patient stratification by PSADT [87, 88]. Hence, it is worth conducting a clinical study to prove the advantage of disease stabilization by melatonin with active monitoring over that by watchful waiting alone in this subgroup of patients with clinically localized prostate cancer. The results of this trial, if promising, will also provide important data to justify larger clinical prevention trials to demonstrate the efficacy of melatonin in primary prostate cancer chemoprevention.

Like many other types of cancer, the aim of advanced or metastatic prostate cancer treatment is palliation rather than cure. ADT, as discussed above, is the current gold standard of treatment for advanced or metastatic prostate cancer [89, 90]. While the androgen-dependent tumour will respond to ADT initially, the majority of castrated patients will suffer relapse of their disease after a median of 18 months. The relapsed tumour then becomes androgen-independent (Fig. 2B). Hence, there is a high unmet clinical need of advanced prostate cancer patients, particularly those resistant to hormonal treatment. It is believed that a greater understanding of the molecular pathogenesis of androgen-independent prostate cancer (also named as hormone-refractory or castration-resistant prostate cancer) will allow a more rational approach to the discovery and development of new treatment options [91]. As a consequence, significant research efforts have been directed towards this goal.

The emergence of androgen-independent prostate cancer has been found to be associated with mutations in the ligand-binding domain of the AR that permit receptor activation by other steroids or antiandrogens, upregulation of ARs accompanying AR gene amplification, and ligand-independent activation of AR by growth factors such as insulin-like growth factor I and cytokines such as interleukin-6 signalling pathway [92]. Clearly, enhanced AR signal transduction in response to ADT plays a very dominant role in the progression of prostate cancer from androgen dependence to androgen independence. Inhibition of enhanced AR signalling would be a rational approach in the prevention or retardation of prostate tumour cell transition from androgen dependence to androgen independence. Given that melatonin/MT1/PKC activation can downregulate activated androgenic signalling by decreasing AR-mediated transcriptional activity through nuclear exclusion of AR [32, 53–57], melatonin appears to be a promising molecule that can be used to slow prostate cancer progression to androgen independence during ADT. It can thus be envisaged that the combined use of ADT and melatonin would be most effective in preventing or delaying the emergence of androgen-independent prostate cancer. This can be tested conveniently by measuring any additional benefits of melatonin over ADT on the lengths of relapse-free survival and the total survival periods of advanced or metastatic prostate cancer patients.

As melatonin has been shown to reduce the toxicities and increase the efficacies of chemotherapeutic drugs when used together with them in cancer patients [93, 94], it is reasonable to predict better patients’ responses towards the recommended docetaxel-based chemotherapy for hormone-refractory prostate cancer [95].


  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence in support of the melatonin hypothesis in prostate cancer
  5. Melatonin signalling in antiproliferation of prostate cancer versus breast cancer epithelial cells
  6. Prostate cancer prevention: role of melatonin
  7. Prostate cancer treatment: role of melatonin
  8. Conclusions
  9. Acknowledgements
  10. References

Collectively, the wealth of scientific evidence available supports the use of melatonin for the prevention and treatment of prostate cancer. There are at least four important properties of melatonin which make it an ideal small-molecule to be tested clinically for its effectiveness in prostate cancer prevention and treatment.

  • 1
    Melatonin acts as an antioxidant, which has been convincingly demonstrated in various experimental models [34, 35, 96], to combat the oxidative stress important in carcinogenesis.
  • 2
    Melatonin activates tumour-suppressive signalling network in prostate cancer cells by upregulating the expression of p27Kip1 [32]. It is noteworthy that mutated PTEN functions leading to downregulated p27Kip1 expression is known to be an important critical event in prostate carcinogenesis and progression [50–52].
  • 3
    Melatonin inhibits AR-mediated transcriptional activation of proliferation-associated genes or gene fusions through nuclear exclusion of AR [32, 53–57]. Of note, activated androgenic signalling is believed to be crucial in providing the mitogenic (oncogenic) stimulation for prostate cancer carcinogenesis as well as the development of hormone-refractory prostate cancer [65, 92].
  • 4
    Melatonin, used as a nutraceutical-like selenium and vitamin E in the USA, is nontoxic, has a high safety margin [97–99], easily synthesized in pharmacologically pure form, nonpatentable, inexpensive and affordable.

There are at least three clinical settings of prostate cancer under which melatonin is likely to become evidence-based treatment of choice: primary cancer prevention, stabilization of clinically-localized prostate cancer of favourable-risk, and in combination with ADT to delay the relapse of hormone-refractory or castration-resistant prostate cancer. As the resource implications in conducting randomized-controlled primary prostate cancer prevention trials are much greater than the other two set of trials, in which much less costly smaller-scale clinical studies will provide the proof-of-concept evidence in humans, it may be more logical to test the primary chemoprevention concept of melatonin first in available genetically modified mouse models of prostate cancer that recapitulate many aspects of human cancer [78, 100]. The results from these mouse model trials will then help the development of clinical protocols for large-scale primary prostate cancer prevention trials. The outlook for translational application of melatonin in cancer therapy has never been more promising [101, 102], particularly in future clinical management of prostate cancer.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence in support of the melatonin hypothesis in prostate cancer
  5. Melatonin signalling in antiproliferation of prostate cancer versus breast cancer epithelial cells
  6. Prostate cancer prevention: role of melatonin
  7. Prostate cancer treatment: role of melatonin
  8. Conclusions
  9. Acknowledgements
  10. References

The author would like to thank past and present laboratory members and collaborators for their contributions to melatonin research in prostate cancer. SYWS's laboratory has been supported by the Neuroendocrinology Research Fund of The University of Hong Kong (HKU), the HKU Foundation for Educational Development and Research and the Research Grants Council of Hong Kong.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence in support of the melatonin hypothesis in prostate cancer
  5. Melatonin signalling in antiproliferation of prostate cancer versus breast cancer epithelial cells
  6. Prostate cancer prevention: role of melatonin
  7. Prostate cancer treatment: role of melatonin
  8. Conclusions
  9. Acknowledgements
  10. References
  • 1
    American Cancer Society. Cancer Facts and Figures 2006. American Cancer Society, Atlanta, 2006.
  • 2
    Reiter RJ. The melatonin rhythm: both a clock and a calendar. Experientia 1993; 49:654664.
  • 3
    Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336:186195.
  • 4
    Lincoln GA, Clarke IJ, Hut RA et al. Characterizing a mammalian circannual pacemaker. Science 2006; 314:19411944.
  • 5
    Panzer A, Viljoen M. The validity of melatonin as an oncostatic agent. J Pineal Res 1997; 22:184202.
  • 6
    Reiter RJ. Mechanisms of cancer inhibition by melatonin. J Pineal Res 2004; 37:213214.
  • 7
    Jung B, Ahmad N. Melatonin in cancer management: progress and promise. Cancer Res 2006; 66:97899793.
  • 8
    Reiter RJ, Gultekin F, Manchester LC et al. Light pollution, melatonin suppression and cancer growth. J Pineal Res 2006; 40:357358.
  • 9
    Cohen M, Lippman M, Chabner B. Role of pineal gland in aetiology and treatment of breast cancer. Lancet 1978; 2:814816.
  • 10
    Danforth DN Jr, Tamarkin L, Lippman ME. Melatonin increases oestrogen receptor binding activity of human breast cancer cells. Nature 1983; 305:323325.
  • 11
    Tamarkin L, Danforth D, Lichter A et al. Decreased nocturnal plasma melatonin peak in patients with estrogen receptor positive breast cancer. Science 1982; 216:10031005.
  • 12
    Hill SM, Blask DE. Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture. Cancer Res 1988; 48:61216126.
  • 13
    Blask DE, Wilson ST, Zalatan F. Physiological melatonin inhibition of human breast cancer cell growth in vitro: evidence for a glutathione-mediated pathway. Cancer Res 1997; 57:19091914.
  • 14
    Sanchez-Barcelo EJ, Cos S, Fernandez R et al. Melatonin and mammary cancer: a short review. Endocr Relat Cancer 2003; 10:153159.
  • 15
    Prener A, Storm HH, Nielsen NH. Cancer of the male genital tract in circumpolar Inuit. Acta Oncol 1996; 35:589593.
  • 16
    Dewailly E, Mulvad G, Pedersen HS et al. Inuit are protected against prostate cancer. Cancer Epidemiol Biomarkers Prev 2003; 12:926927.
  • 17
    Feychting M, Ouml;sterlund B, Ahlbom A. Reduced cancer incidence among the blind. Epidemiology 1998; 9:490494.
  • 18
    Pukkala E, Ojamo M, Rudanko SL et al. Does incidence of breast cancer and prostate cancer decrease with increasing degree of visual impairment. Cancer Causes Control 2006; 17:573576.
  • 19
    Iguchi H, Kato KI, Ibayashi H. Age-dependent reduction in serum melatonin concentrations in healthy human subjects. J Clin Endocrinol Metab 1982; 55:2729.
  • 20
    Sack RL, Lewy AJ, Erb DL et al. Human melatonin production decreases with age. J Pineal Res 1986; 3:379388.
  • 21
    Waldhauser F, Weiszenbacher G, Tatzer E et al. Alterations in nocturnal serum melatonin levels in humans with growth and aging. J Clin Endocrinol Metab 1988; 66:648652.
  • 22
    Zhao ZY, Xie Y, Fu YR et al. Aging and the circadian rhythm of melatonin; a cross-sectional study of Chinese subjects 30–110 yr of age. Chronobiol Int 2002; 19:11711182.
  • 23
    Bartsch C, Bartsch H, Schmidt A et al. Melatonin and 6-sulfatoxymelatonin circadian rhythms in serum and urine of primary prostate cancer patients; evidence for reduced pineal activity and relevance of urinary determinations. Clin Chim Acta 1992; 209:153167.
  • 24
    Xi SC, Tam PC, Brown GM et al. Potential involvement of mt1 receptor and attenuated sex-steroid-induced calcium influx in the direct anti-proliferative action of melatonin on androgen-responsive LNCaP human prostate cancer cells. J Pineal Res 2000; 29:172183.
  • 25
    Xi SC, Siu SWF, Fong SW et al. Inhibition of androgen-sensitive LNCaP prostate cancer growth in vivo by melatonin: association of antiproliferative action of the pineal hormone with mt1 receptor protein expression. Prostate 2001; 6:5261.
  • 26
    Siu SWF, Lau KW, Tam PC et al. Melatonin and prostate cancer cell proliferation: interplay with castration, epidermal growth factor, and androgen sensitivity. Prostate 2002; 52:106122 [Erratum, Prostate 2002; 52:252].
  • 27
    Lupowitz Z, Zisapel N. Hormonal interactions in human prostate tumor LNCaP cells. J Steroid Biochem Mol Biol 1999; 68:8388.
  • 28
    Moretti RM, Marelli MM, Maggi R et al. Antiproliferative action of melatonin on human prostate cancer LNCaP cells. Oncol Rep 2000; 7:347351.
  • 29
    Sainz RM, Mayo JC, Tan DX et al. Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism. Prostate 2005; 63:2943.
  • 30
    Marelli MM, Limonta P, Maggi R et al. Growth-inhibitory activity of melatonin on human androgen-independent DU 145 prostate cancer cells. Prostate 2000; 45:238244.
  • 31
    Shiu SYW, Law IC, Lau KW et al. 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.
  • 32
    Tam CW, Mo CW, Yao KM et al. Signaling mechanisms of melatonin in antiproliferation of hormone-refractory 22Rv1 human prostate cancer cells: implications for prostate cancer chemoprevention. J Pineal Res 2007; 42:191202.
  • 33
    Reppert SM, Weaver DR, Godson C. Melatonin receptors step into the light; cloning and classification of subtypes. Trends Pharmacol Sci 1996; 17:100102.
  • 34
    Tan DX, Reiter RJ, Manchester LC et al. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2002; 2:181197.
  • 35
    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.
  • 36
    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.
  • 37
    Sauer LA, Dauchy RT, Blask DE et al. 13-Hydroxyoctadecadienoic acid is the mitogenic signal for linoleic acid-dependent growth in rat hepatoma 7288CTC in vivo. Cancer Res 1999; 59:46884692.
  • 38
    Blask DE, Sauer LA, Dauchy RT et al. Melatonin inhibition of cancer growth in vivo involves suppression of tumor fatty acid metabolism via melatonin receptor-mediated signal transduction events. Cancer Res 1999; 59:46934701.
  • 39
    Sauer LA, Dauchy RT, Blask DE. Melatonin inhibits fatty acid transport in inguinal fat pads of hepatoma 7288CTC-bearing and normal Buffalo rats via receptor-mediated signal transduction. Life Sci 2001; 68:28352844.
  • 40
    Blask DE, Dauchy RT, Sauer LA et al. Melatonin uptake and growth prevention in rat hepatoma 7288CTC in response to dietary melatonin: melatonin receptor-mediated inhibition of tumor linoleic acid metabolism to the growth signaling molecule 13-hydroxyoctadecadienoic acid and the potential role of phytomelatonin. Carcinogenesis 2004; 25:951960.
  • 41
    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.
  • 42
    Ram PT, Dai J, Yuan L et al. Involvement of the mt1 melatonin receptor in human breast cancer. Cancer Lett 2002; 179:141150.
  • 43
    Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal. Endocrine 2005; 27:179188.
  • 44
    Martin V, Herrera F, Carrera-Gonzalez P et al. Intracellular signaling pathways involved in the cell growth inhibition of glioma cells by melatonin. Cancer Res 2006; 66:10811088.
  • 45
    Sanchez-Barcelo EJ, Cos S, Mediavilla D et al. Melatonin-estrogen interactions in breast cancer. J Pineal Res 2005; 38:217222.
  • 46
    Cos S, Gonzalez A, Martinez-Campa C et al. Estrogen-signaling pathway: a link between breast cancer and melatonin oncostatic actions. Cancer Detect Prev 2006; 30:118128.
  • 47
    Lloyd RV, Erickson LA, Jin L et al. p27kip1: A multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. Am J Pathol 1999; 154:313323.
  • 48
    Mediavilla MD, Cos S, Sanchez-Barcelo EJ. Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells in vitro. Life Sci 1999; 65:415420.
  • 49
    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.
  • 50
    Fernandez PL, Arce Y, Farre X et al. Expression of p27/kip1 is down-regulated in human prostate carcinoma progression. J Pathol 1999; 187:563566.
  • 51
    Sun H, Lesche R, Li DM et al. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci U S A 1999; 96:61996204.
  • 52
    Graff JR, Konicek BW, Mcnulty AM et al. Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem 2000; 275:2450024505.
  • 53
    Rimler A, Culig Z, Lupowitz Z et al. Nuclear exclusion of the androgen receptor by melatonin. J Steroid Biochem Mol Biol 2002; 81:7784.
  • 54
    Rimler A, Culig Z, Levy-Rimler G et al. Melatonin elicits nuclear exclusion of the human androgen receptor and attenuates its activity. Prostate 2001; 49:145154.
  • 55
    Lupowitz Z, Rimler A, Zisapel N. Evaluation of signal transduction pathways mediating the nuclear exclusion of the androgen receptor by melatonin. Cell Mol Life Sci 2001; 58:21292135.
  • 56
    Sampson SR, Lupowitz Z, Braiman L et al. Role of protein kinase Calpha in melatonin signal transduction. Mol Cell Endocrinol 2006; 252:8287.
  • 57
    Rimler A, Lupowitz Z, Zisapel N. Differential regulation by melatonin of cell growth and androgen receptor binding to the androgen response element in prostate cancer cells. Neuro Endocrinol Lett 2002; 23 (Suppl. 1): 4549.
  • 58
    Klein EA. Can prostate cancer be prevented? Nat Clin Pract Urol 2005; 2:2431.
  • 59
    Ekman P. Genetic and environmental factors in prostate cancer genesis: identifying high-risk cohorts. Eur Urol 1999; 35:362369.
  • 60
    Nwosu V, Carpten J, Trent JM et al. Heterogeneity of genetic alterations in prostate cancer: evidence of the complex nature of the disease. Hum Mol Genet 2001; 10:23132318.
  • 61
    Zlotta AR, Schulman CC. Clinical evolution of prostatic intraepithelial neoplasia. Eur Urol 1999; 35:498503.
  • 62
    Sakr WA, Haas GP, Cassin BF et al. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 1993; 150:379385.
  • 63
    Sakr WA, Grignon DJ, Haas GP et al. Age and racial distribution of prostatic intraepithelial neoplasia. Eur Urol 1996; 30:138144.
  • 64
    Nelson WG, De Marzo AM, Isaacs WB. Prostate cancer. N Engl J Med 2003; 349:366381.
  • 65
    Buchanan G, Irvine RA, Coetzee GA et al. Contribution of the androgen receptor to prostate cancer predisposition and progression. Cancer Metastasis Rev 2001; 20:207223.
  • 66
    Tomlins SA, Rhodes DR, Perner S et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310:644648.
  • 67
    Rubin MA, Chinnaiyan AM. Bioinformatics approach leads to the discovery of the TMPRSS2:ETS gene fusion in prostate cancer. Lab Invest 2006; 86:10991102.
  • 68
    Cerveira N, Ribeiro FR, Peixoto A et al. TMPRSS2-ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions. Neoplasia 2006; 8:826832.
  • 69
    Thompson IM, Goodman PJ, Tangen CM et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003; 349:215224.
  • 70
    Nickel JC. Comparison of clinical trials with finasteride and dutasteride. Rev Urol 2004; 6 (Suppl. 9): S31S39.
  • 71
    Thomas LN, Douglas RC, Vessey JP et al. 5alpha-reductase type 1 immunostaining is enhanced in some prostate cancers compared with benign prostatic hyperplasia epithelium. J Urol 2003; 170:20192025.
  • 72
    Nelson WG, De Marzo AM, Deweese TL et al. Preneoplastic prostate lesions: an opportunity for prostate cancer prevention. Ann N Y Acad Sci 2001; 952:135144.
  • 73
    Miller ER III, Pastor-Barriuso R, Dalal D et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005; 142:3746.
  • 74
    Steck PA, Pershouse MA, Jasser SA et al. Identification of a candidate tumor suppressor gene MMAC1 at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997; 15:356362.
  • 75
    Gray IC, Stewart LM, Phillips SM et al. Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN. Br J Cancer 1998; 78:12961300.
  • 76
    Di Cristofano A, Pesce B, Cordon-Cardo C et al. Pten is essential for embryonic development and tumour suppression. Nat Genet 1998; 19:348355.
  • 77
    Trotman LC, Niki M, Dotan ZA et al. Pten dose dictates cancer progression in the prostate. PLoS Biol 2003; 1:E59.
  • 78
    Wang S, Gao J, Lei Q et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 2003; 4:209221.
  • 79
    Sharpless NE, Depinho RA. Cancer: crime and punishment. Nature 2005; 436:636637.
  • 80
    Fernandez PL, Arce Y, Farre X et al. Expression of p27/Kip1 is down-regulated in human prostate carcinoma progression. J Pathol 1999; 187:563566.
  • 81
    Doganavsargil B, Simsir A, Boyacioglu H et al. A comparison of p21 and p27 immunoexpression in benign glands, prostatic intraepithelial neoplasia and prostate adenocarcinoma. BJU Int 2006; 97:644648.
  • 82
    Di Cristofano A, De Acetis M, Koff A et al. Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nat Genet 2001; 27:222224.
  • 83
    Chen Z, Trotman LC, Shaffer D et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 2005; 436:725730.
  • 84
    Aus G, Abbou CC, Pacik D et al. EAU guidelines on prostate cancer. Eur Urol 2001; 40:97101.
  • 85
    Wirth MP, Hakenberg OW. Curative treatment of prostate cancer. Urol Int 1999; 63:7279.
  • 86
    Barry MJ. Clinical practice. Prostate-specific-antigen testing for early diagnosis of prostate cancer. N Engl J Med 2001; 344:13731377.
  • 87
    Klotz L. Active surveillance for prostate cancer: for whom? J Clin Oncol 2005; 23:81658169.
  • 88
    Klotz L. Active surveillance versus radical treatment for favorable-risk localized prostate cancer. Curr Treat Options Oncol 2006; 7:355362.
  • 89
    Miyamoto H, Messing EM, Chang C. Androgen deprivation therapy for prostate cancer: current status and future prospects. Prostate 2004; 61:332353.
  • 90
    Debes JD, Tindall DJ. Mechanisms of androgen-refractory prostate cancer. N Engl J Med 2004; 351:14881490.
  • 91
    Chang SS, Benson MC, Campbell SC et al. Society of Urologic Oncology position statement: redefining the management of hormone-refractory prostate carcinoma. Cancer 2005; 103:1121.
  • 92
    Attard G, Sarker D, Reid A et al. Improving the outcome of patients with castration-resistant prostate cancer through rational drug development. Br J Cancer 2006; 95:767774.
  • 93
    Reiter RJ, Tan DX, Sainz RM et al. Melatonin: reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmacol 2002; 54:12991321.
  • 94
    Lissoni P. Is there a role for melatonin in supportive care? Support Care Cancer 2002; 10:110116.
  • 95
    Collins R, Trowman R, Norman G et al. A systematic review of the effectiveness of docetaxel and mitoxantrone for the treatment of metastatic hormone-refractory prostate cancer. Br J Cancer 2006; 95:457462.
  • 96
    Vijayalaxmi, Reiter RJ, Tan DX et al. Melatonin as a radioprotective agent: a review. Int J Radiat Oncol Biol Phys 2004; 59:639653.
  • 97
    Seabra ML, Bignotto M, Pinto LR et al. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res 2000; 29:193200.
  • 98
    Buscemi N, Vandermeer B, Hooton N et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ 2006; 332:385393.
  • 99
    Buscemi N, Vandermeer B, Pandya R et al. Melatonin for Treatment of Sleep Disorders. Evidence Report/Technology Assessment No. 108. (Prepared by the University of Alberta Evidence-based Practice Center, under Contract No. 290-02-0023.) AHRQ Publication No. 05-E002-2. Agency for Healthcare Research and Quality, Rockville, MD, 2004.
  • 100
    Carver BS, Pandolfi PP. Mouse modeling in oncologic preclinical and translational research. Clin Cancer Res 2006; 12:53055311.
  • 101
    Vijayalaxmi, Thomas CR Jr, Reiter RJ et al. Melatonin: from basic research to cancer treatment clinics. J Clin Oncol 2002; 20:25752601.
  • 102
    Mills E, Wu P, Seely D et al. Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis. J Pineal Res 2005; 39:360366.