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The inhibitory effect of melatonin on human prostate cancer


Prostate cancer (PCa) is one of the most commonly diagnosed human cancers in males. Nearly 191,930 new cases and 33,330 new deaths of PCa are estimated in 2020. Androgen and androgen receptor pathways played essential roles in the pathogenesis of PCa. Androgen depletion therapy is the most used therapies for primary PCa patients. However, due to the high relapse and mortality of PCa, developing novel noninvasive therapies have become the focus of research. Melatonin is an indole-like neurohormone mainly produced in the human pineal gland with a prominent anti-oxidant property. The anti-tumor ability of melatonin has been substantially confirmed and several related articles have also reported the inhibitory effect of melatonin on PCa, while reviews of this inhibitory effect of melatonin on PCa in recent 10 years are absent. Therefore, we systematically discuss the relationship between melatonin disruption and the risk of PCa, the mechanism of how melatonin inhibited PCa, and the synergistic benefits of melatonin and other drugs to summarize current understandings about the function of melatonin in suppressing human prostate cancer. We also raise several unsolved issues that need to be resolved to translate currently non-clinical trials of melatonin for clinic use. We hope this literature review could provide a solid theoretical basis for the future utilization of melatonin in preventing, diagnosing and treating human prostate cancer.

Video abstract


Prostate cancer

Prostate cancer (PCa) is one of the most commonly diagnosed cancers in males [1]. The American Cancer Society estimated 191,930 new cases and 33,330 new deaths of PCa in 2020 [1]. Sadly, although there is a downward trend in the number of new cases and deaths for several decades [1], conditions seem to deteriorate during the past 3 years (2017–2019) [2,3,4]. The estimated new cases per year increased from 161,360 in 2017 [2] to 174,650 in 2019 [4] and the annual death increased from 26,730 in 2017 [2] to 31,620 in 2019 [4]. Androgen and androgen receptor (AR) pathways played essential roles in the pathogenesis of PCa [5]. Aberrant AR mutations [6], intratumoral androgen synthesis [7], and abnormal AR splice variants [8] are negative inducers of PCa. Currently, the most used therapy for hormone-naive PCa cancer patients is androgen depletion therapy (ADT). ADT could lead patients to an initially beneficial stage with tumor extinction, but eventually the majority of hormone-naive PCa become less sensitive to ADT and progress into a more malignant stage, the castration resistant prostate cancer (CRPC). CRPC not only is resistant to castration treatment but also exhibits other negative features such as distant metastasis [9] and neuroendocrine differentiation. Due to the high relapse and mortality of PCa, developing novel noninvasive therapies have become the focus of research. Among the artificial and natural compounds, melatonin is of great potential for treating PCa.


Melatonin (N-acetyl-methoxy-tryptamine), an indole-like neurohormone, is primarily synthesized in human pineal gland. Besides brain, melatonin is also found to be synthesized in lung [10], gastrointestinal tract [11], lens [12], kidney [13] and pancreas [14]. Daily circadian rhythm is the main regulator that modulates the biosynthesis of melatonin [15]. Optical signals promote the breakdown of melanopsin in retinal photoreceptive ganglion cells, thus blocking the synthesis of melatonin [16]. Consequently, melatonin in circulation is low or even undetectable during the daytime [17]. On the contrary, melatonin is mainly produced during the dark phase, and the maximal plasma level is detected 4–5 h after darkness onset [18]. Alternating light–dark cycles or improper exposure to light can disrupt the inner circadian rhythm and thus decrease nocturnal melatonin synthesis [19, 20]. The most prominent function of melatonin is its high efficiency as a radical scavenger [21]. The amphiphilic nature allows melatonin to easily enter mitochondrion [22,23,24]. Through scavenging free radicals, activating uncoupling proteins and maintaining mitochondrion membrane potential, melatonin could effectively maintain intracellular redox homeostasis [25, 26]. Recently, mitochondrion is pointed out to be the potential site where melatonin is originally generated [27]. The other bio-functions of melatonin included but not limited to regulating metabolism [28], promoting vascular reactivity [29], elevating immune response [10], preventing DNA damage [30], inducing apoptosis [31] and autophagy [32,33,34] and inhibiting tumor proliferation [34,35,36].

The intake of melatonin from daily diet or drug supplements

Daily diet can provide a certain amount of melatonin for human body ranging from picograms to milligrams per gram. For foods of animal origin, eggs, fish and milk contained a higher concentration of melatonin [37]. Interestingly, milking time was a key factor that determined the concentration of melatonin in milk [38]. According to Milagres [39], milk produced at night contained a relatively higher concentration of melatonin than milk produced during the daytime. For foods of plant or fruit sources, the generative organs tended to contain a higher degree of melatonin, especially the seeds, which were proposed as having a considerably higher concentration of melatonin than other vegetable tissues [40]. In a study including 12 healthy male volunteers, the volunteers were asked to drink juice extracted from 1 kg of orange or pineapple or two whole bananas for breakfast and the serum melatonin concentration reached the highest level at the second hour after breakfast [41]. Moreover, serum antioxidant capacity of the volunteers was also obviously improved and was significantly correlated with serum melatonin concentration for all the three fruits tested.

Moreover, melatonin can also be obtained from drug supplements. In Europe and the United States, melatonin-supplement drugs were wildly used to alleviate jet-lag or to improve sleep quality. Noteworthy, traditional Chinese medicine also contained a degree of melatonin ranging from a few to several thousand nanograms per gram, revealing that they were ideal natural origins of this health-friendly hormone [42].

In a word, people’s daily diet or commercial melatonin-supplement drugs are good sources of melatonin and a reasonable combination of food ingredients could bring benefits to human body.


Considering that the number of reviews of the inhibitory effect of melatonin on PCa in recent 10 years is not commensurate with the advances acquired in relevant fields, we write this literature review to fill this gap. Herein, we systematically discuss the anti-PCa property of melatonin to summarize current understandings about its inhibitory effect on human PCa and uncover the possibility of translating experimental findings into clinical treatment.

The inhibitory property of melatonin

The correlation between melatonin disruption and risk of PCa

As described above, the release of melatonin is under the control of circadian rhythm and light exposure. Disturbed circadian rhythm of light and decreased serum level of melatonin is highly correlated to various types of human cancers [43,44,45,46,47]. Notably, the incidence of cancer in blind people is surprisingly lower than in normal people without visual impairment [48,49,50,51], which may be a result of a higher level of melatonin. In 2007, the World Health Organization once concluded that “shift-work that involves circadian disruption is probably carcinogenic to humans” [52].

Actually, the potential correlation between melatonin and the risk of PCa has arisen people’s attention as early as 1985. A study conducted in healthy young men, BPH patients and PCa patients showed that the serum level of melatonin waves the most dramatically compared with other hormones, such as prolactin or growth hormone, reminding people of an unexpected association between melatonin and human PCa [53].

Recently, epidemiologic surveys have exhibited that disrupted secretion and low blood levels of melatonin may elevate the risk of PCa in humans (Table 1). According to Papantoniou et al. [54], they discovered a higher incidence of PCa among people who had worked at least for 1 year in night shift work. Moreover, in a 1693-people-involved study, Wendeu-Foyet et al. [55] reported that male workers who underwent permanent night work for at least 20 years were more inclined to suffer from advanced PCa. In addition, along with cortisol, another hormone that is related to the circadian cycle, Tai et al. [56] detected a higher level of PSA while a lower level of aMT6s (a metabolite of melatonin) in PCa patients than healthy men. Besides night shift work, improper exposure to light may also be responsible for the initiation of PCa. A case–control study in South Korea [57] found light pollution is an independent risk factor of PCa. However, supplementing melatonin in nocturnal drinking water could recover melatonin to a normal level and reverse these negative effects [43].

Table 1 The correlation of melatonin disruption and risk of prostate cancer
Table 2 The synergistic use of melatonin and other drugs or therapies in treating prostate cancer

The underlying explanation might be that light at night could suppress melatonin biosynthesis and damage normal metabolism thus activating aberrant proliferative activity [58]. While changing the wavelength of light to a proper range, for example, blue light could amplify the nighttime melatonin level and inhibit the metabolism and proliferative activities of PCa cells [59] (Table 2).

Inspiringly, due to the significance of personalized PCa screening has been increasingly prominent, traditional PSA screening strategies are urged to be developed [60] and considering the serum level of melatonin or the level of its metabolite is closely related to the risk of PCa, it deserves further exploring that whether the combined detection of PSA and melatonin can further improve the efficiency of existing PCa screening methods.

Melatonin and androgen receptor (AR) pathway

The AR pathway

AR pathway, including androgen, AR and AR co-regulators, is of primary significance in the biogenesis and development of PCa [61,62,63]. Androgen synthesized in testis hold nearly 60% of the gross in prostate gland [64]. The rest 30% is mainly secreted from the zona reticularis of adrenal glands [65, 66]. Androgen acts as a ligand in this pathway and activates downstream signals by binding to androgen receptor (AR), which is also known as a nuclear transcription factor. AR has four domains: the C-terminal ligand-binding domain (LBD); the centrally-located DNA-binding domain (DBD); the N-terminal transactivational domain (NTD) and the hinge region that separates the LBD and the DBD. The interaction between LBD and NTD is essential for AR to maintain its stability. Unliganded AR mainly resided in the cytoplasm [67, 68] remaining an inactive status being sequestered by multiple heat shock proteins or cytoskeletal proteins [69]. After being coupled with androgen, the complex is triggered to dissociate and the following interaction between AR and Filamin A promotes the nuclear translocation of AR. Then AR binds to specific DNA sequence motifs, the androgen response elements (AREs), in the promoter and enhancer region of these hormone-dependent genes to initiate transcription.

The role of AR in PCa

The role of AR in driving the initiation and progression of PCa has been well established. More concretely, AR participants in the development and drug-resistance of PCa mainly via three routines. The first one is aberrant AR mutations. Mutations in the LBD domain of AR, such as residue 701 (L701H) and residue 877 (T877A), are related to distant metastasis [70] and abnormal activation of AR [71, 72]. Another three mutations, L702H, W742C and H875Y, are identified to be associated with the development of CRPC [73, 74]. The second is intratumoral androgen synthesis. Although castration can significantly reduce circulating testosterone levels, the total amount of serum androgen metabolites and androgen isolated from PCa tissues still have pathological effects, indicating a non-testicular source of androgen [65, 75]. Indeed, CYP11A1, a cholesterol cleavage enzyme, is overexpressed in CRPC tissues and participants in the process of a weak androgen synthesis [7]. Last but not least is the abnormal expression of AR and AR splice variants (AR-Vs). The aberrant amplification of AR could hypersensitize PCa cells to a low level of androgen [76] and cause resistance to anti-androgen drugs like bicalutamide [77]. AR-Vs, including AR-V1, AR-V567es, and AR-V7, are truncated forms of AR protein lacking the LBD [78] and have frequently been detected in CRPC tissues. AR-V7 is the most thoroughly explored one due to its abundance and is currently utilized as a clinical biomarker for therapy selection in men with distant metastasis [79]. Due to the loss of LBD, AR-Vs can escape the regulation of current hormone therapies [80]. Interestingly, since they retain the DBD, AR-Vs are still capable of regulating the transcription of downstream genes and further promote the occurrence of CRPC [80].

The adverse effect of melatonin on AR pathway

Melatonin has been demonstrated to modulate the transcription activity of the estrogen receptor (ER) and inhibit the expression of the estradiol-dependent gene [81, 82]. However, melatonin does not damage the activation of AR by androgen. AR mainly works in the nuclear and the right localization of AR is indispensible for its biological activity. Nuclear exclusion is caused by mutations in the DBD of AR and results in loss of androgen sensitivity [83]. Moreover, the mislocation of AR is confirmed to promote human diseases such as spinal bulbar muscular atrophy (SBMA) [84, 85].

Rimler et al. [86] showed that melatonin treatment could increase the protein level of AR but not inhibit its binding capacity as a transcription factor. Furthermore, although the overall amount of AR in the cells was elevated, AR content present in nuclear was unexpectedly reduced. Another two studies by Rimler et al. [87, 88] also confirmed that the regulation of melatonin on AR is mainly via promoting its nuclear translocation rather than blocking its expression level or competing the steroid binding sites. According to Lupowitz et al. [89] and Rimler et al. [90], the binding of melatonin and its receptor stimulated Gi-type G proteins to enhance the production of cGMP. Elevated cGMP induces intracellular flux of Ca2+ with the following activation of PKC. Activated PKC finally promoted the exclusion of AR with an unclarified Gq-signaling pathway. Additionally, the concomitant activity of RGS proteins exerts adverse effects on the melatonin-triggered AR exclusion. The mechanism diagram of AR nuclear exclusion is shown in Fig. 1.

Fig. 1

Adverse effect of melatonin on the AR pathway. (1) The AR pathway. Androgen triggered the dissociation of AR and HSPs. AR and androgen formed complexes and were transported into nuclear. Nuclear AR complexes bound to the ARE region of hormone-dependent genes to start the transcription. (2) Melatonin mediated the AR nuclear exclusion via a Gi/cGMP/Ca2+/PKC pathway. Melatonin stimulated Gi protein to enhance the production of cGMP. cGMP induced the intracellular flux of Ca2+. Ca2+ activated PKC and PKC promoted the nuclear exclusion of AR. RGS proteins (RGS4, RGS10) exerted adverse effects on this pathway. (3) The potential involvement of Gq protein in AR nuclear exclusion. Melatonin activated phospholipase C (PLC) to generate inositoltriphosphate (IP3) and diacylglycerol (DAG) which contributed to the intracellular flux of Ca2+. Activated Gq protein presumably stimulated PLC or (PLD) to promote AR nuclear exclusion, and the process was inhibited by RGS4

The findings presented above contribute to a better understanding of the androgen inhibitor action of melatonin and provide solid theories for exploring new AR localization regulators to improve the drug sensitivity of PCa.

The benefits of melatonin on androgen depletion therapy

Because of the primary role of AR pathway in fueling the initiation and growth of PCa, androgen depletion therapy (ADT) or castration therapy has become the first-line treatment for PCa. Castration can be performed via two methods, bilateral orchiectomy or chemical drugs, to reduce the serum testosterone to an extremely low level (≤ 50 ng/dL) [91]. However, ADT is only a palliative therapy but not a curative therapy for PCa p atients. Although there is a positive feedback rate of 80–90% in the early stage of treatment [92], the majority of patients will finally transform into the stage of CRPC, a more aggressive and lethal stage of PCa. The average overall survival of CRPC patients with distant metastasis is 1.5 years [93].

Although the level of androgen in circulation is extremely low, a number of studies still show that androgen and AR pathway remain functional in CRPC cells. A gene expression analysis of PCa samples during hormonal therapy unexpectedly revealed that the overall expression patterns of CRPC were nearly identical to those of the untreated samples [94]. For example, FKBP5, a hormone-responsive gene regulated by AR, is identified to be re-expressed in CRPC samples even though under an androgen-depleted condition [94, 95]. Moreover, studies inhibiting AR expression surprisingly showed that AR is indispensable for PCa cells to maintain the growth in vitro and in castrated mice [96,97,98,99]. In general, CRPC is not totally hormone refractory and the AR pathway remained an important therapeutic target for CRPC [100].

Notably, some studies have shown positive outcomes by adding melatonin to ADT. Siu et al. [101] reported that melatonin can strengthen the inhibitory effect of castration therapy on androgen-sensitive PCa cells. By establishing a castrated-model, they found melatonin significantly slowed the appearance and growth rate combined with castration therapy compared with the untreated group. Along with their previous observations, melatonin could inhibit the proliferation of LNCaP cells both in vitro under an androgen-free condition [102] and in intact mice [103]. These data supported an ideal synergistic benefit of melatonin and castration in clinical use. Besides androgen-sensitive prostate cancers, melatonin also exerts a positive effect on hormone-refractory PCa cells. Liu et al. [104] reported that melatonin can delay the progression of castration resistance in advanced PCa via interrupting the reciprocal interaction between AR-V7 and NF-κB (shown in Fig. 2). Moreover, the concomitant administration of the melatonin with castration therapy in CRPC patients could induce an obvious decrease in PSA serum levels, elevate platelet count to a standard value and prolong the overall survival span [105]. This pilot study demonstrated the feasibility of melatonin repletion to overcome the loss of efficacy of castration therapy and improve the clinical effect for advanced PCa patients. Moreover, as Gennady et al. [106] reported, long-term use of melatonin was an independent predictive factor and could reduce the event of death to lower than 50% in PCa patients with advanced-stage, even though it did not show ideal effects on patients with a favorable and intermediate prognosis.

Fig. 2

The MT1 pathway. (1) Melatonin up-regulated p27kip1 via blocking the activity of NF-κB. MT1 receptor activated Gαs and Gαq. Gαq directly activated PKC and Gαs indirectly activated PKA via elevating cAMP. PKC and PKA inhibited the binding ability of NF-κB to the promoter region of p27Kip1 gene. (2) Melatonin decreased the PSA level with an attenuated Ca2+ influx. Activated PKC inhibited the promoting effect of DHT and AR on KLK3 (PSA gene). MT1 receptor inhibited melatonin-responsive calmodulin to modulate L-type Ca2+ channel. (3) Melatonin interrupted the bi-directional positive interactions between AR-V7 and NF-κB. The MT 1 receptor-mediated inhibition on NF-κB decreased the formation of AR-V7 and thus blocking the interactions between AR-V7 and NF-κB

“The treatment of castration-resistant prostate cancer (CRPC) has entered a renaissance era” [107] and considering the fact that the majority of patients will recur and develop into an advanced stage although with an early effective period, there is an urgent need for original, efficacious, secure, and affordable therapies [108, 109]. The results described above highlights the bright future of synergistic interactions between melatonin and ADT in clinical utilization.

Melatonin and MT1 signaling pathway

Generally, it is well-established that there exist two classical types of melatonin receptors in cells, the nuclear RZR/ROR receptors and the membrane-bound MT1 receptors and MT2 receptors. The nuclear RZR/ROR receptors are the relatively less examined ones that are reported to function in the nucleus. The MT1 receptors and MT2 receptors belong to a small sub-family of the GPCR superfamily [110,111,112] and these two membrane-bound receptors trigger most of the signaling pathways of melatonin. The signaling pathways activated by melatonin receptors here we discuss are dependent on tissue context [113, 114] which made it hard to attribute the anti-cancer ability of melatonin to one specific receptor. For example, it was firstly believed that melatonin induces cell apoptosis in colon tumors mainly through the nuclear RZR/ROR receptors [115, 116], while later reports showed that the MT2 receptors also mediated the anti-tumor property on intestinal cancers [116, 117]. And in breast cancers, melatonin was reported to exert its oncostatic action mainly via its MT1 receptors [118, 119].

In PCa, reports showed that MT1 receptors mediated the anti-tumor events of melatonin. Xi et al. [102] reported that melatonin at a pharmacological concentration could inhibit LNCaP cell growth via MT1 receptors with an attenuated Ca2+ influx and the consequent decrease in the level of PSA in the supernatant fluids. Moreover, in another study, Xi et al. [103] also reported that besides causing retarded proliferation of LNCaP cells xenograft in nude mice, mean decreases of 51.7% and 38.7% in tumor volumes were recorded in mice given daily melatonin injection initiated 10 days pre- and post-tumor cell transplantation, respectively. Moreover, cell proliferation markers, the PCNA and cyclin A, decreased obviously after melatonin treatment in LNCaP cells. Besides using standard cell lines, a proof-of-concept translational study using clinical samples showed clear evidence that MT1 signaling is crucial for melatonin to exert its anti-tumor function [120]. Immunohistochemistry assays demonstrated that the receptor subtype of the hormone-refractory patient was identical to the MT1 receptors in PC3 cells. And clinical observations showed that 5 mg melatonin per day not only stabilized the PSA level for almost 6 weeks but also retarded the biological development of the disease with a 23% increase in PSA double time and the platelet count is maintained at a relatively low-risk level.

To date, although none specific genes or chromosomal regions have been indicated to be responsible for PCa initiation, the loss of p27Kip1 was proved to have a major significance in the initiation and maintenance of PCa [121, 122]. p27Kip1 is one of the best-known tumor suppressors which functions as a cyclin-dependent kinase inhibitor preventing cells from entering the G1 phase. Several reports have confirmed that p27Kip1 expression level is adversely associated with the prognosis of PCa [123, 124]. Recently, a series of studies demonstrated the steps of how melatonin up-regulates the p27Kip1 expression [125,126,127]. Firstly, upon binding with melatonin, two G proteins, Gαs and Gαq, were continuously activated. Then Gαq directly activated PKC, while Gαs indirectly activated PKA via increasing intracellular cAMP level. Next, the co-activated PKA and PKC inhibited the DNA binding ability of NF-κB to the promoter region of p27Kip1 gene, thus abolishing the repressing effect of NF-κB on p27Kip1. In addition, activated PKC was also capable of decreasing the PSA level by inhibiting the promoting effect of DHT mediated by AR. Thus, by directly up-regulating p27Kip1 and indirectly decreasing the PSA level (Fig. 2), melatonin exerted its latent capacity for preventing and treating prostate cancers.

Melatonin and PCa metabolism

Tumorigenesis-associated metabolism, a key phenotype change during the oncogenic transformation, offers tumor cells survival opportunities to gain indispensable substances from a relatively nutrient-deficient environment. Most human solid tumors share the most common feature, the Warburg effect, markedly higher consumption of glucose compared with the surrounding normal tissue cells [128,129,130]. The prostate gland is a secretory organ that synthesizes and secrets metabolically distinct prostatic fluid containing a high concentration of citrate. Commonly, cells rely on citrate to proceed with the Krebs cycle for the progression of aerobic respiration and NADPH production [131]. While normal prostate cells do not undergo the classical oxidative phosphorylation and are programmed to undergo a particular and extremely inefficient citrate-oriented metabolism transforming glucose into citrate, then citrate is secreted as a part of the seminal liquid [132, 133]. Nevertheless, primary PCa cells turn to favor oxidative phosphorylation instead of enhancing glycolysis [133, 134]. The malignant cells are reprogrammed to oxidize citrate and complete the tricarboxylic acid cycle, thus transforming into energy-efficient malignant cells [135,136,137]. The consequently low level of citrate is also regarded as a potential non-invasive biomarker for PCa early diagnosis [138]. Interestingly, this alteration is just an early-stage event during the malignant progression. When PCa cells develop into metastatic or castration-resistant stages, they begin to exert the Warburg effect and have a high glucose consumption [139, 140]. Notably, the low level glycolysis may be the underlying reason why even the leading-edge instrument like FDG-PET should omit the hidden lesions of PCa in the early stage [140, 141].

It was widely hypothesized that melatonin enters freely into human cells via passive diffusion across the cellular lipid bilayer due to its amphiphilic nature [142, 143]. However, even though many reports have demonstrated that melatonin has a direct function in inhibiting tumor proliferation, its concentration does not equilibrate outside and inside cells. So there exists an underlying facilitated diffusion or an active process rather than simple passive diffusion. A series of studies by Hevia et al. explained the detailed mechanism. Firstly, they found blocking protein synthesis could unexpectedly inhibit melatonin uptake in PCa cells but extracellular Ca2+/K+ alterations failed to modify the profile of melatonin uptake [144]. Furthermore, they confirmed the role of GLUT1 in transporting melatonin into PCa cells [145]. Docking simulation assays revealed that melatonin and glucose share the same binding sites in GLUT1. Melatonin can suppress the uptake of glucose through competitive inhibition and regulates GLUT1 gene expression in PCa cells. In vivo study also confirm that glucose supplementation accelerated PCa growth in TRAMP mice while adding melatonin to drinking water reversed glucose-triggered tumor growth and expanded the lifespan of tumor-bearing mice. Previous studies also demonstrated that GLUT1 is overexpressed in PCa cells and is highly correlated with cancer proliferation and tumor malignancy [146,147,148,149].

Mitochondrion is regarded as the “energy factory” inside cells where the oxidative phosphorylation and electron transport chain (ETC) proceed. At the same time while ATP is being produced, some unwanted by-products, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), are also released. The high affinity to mitochondrion renders mitochondrion a biological target of melatonin [24, 150]. As Huo et al. [151] reported, the transmembrane transportation of melatonin into mitochondrial promoted its oncostatic effect on human PCa cells. PEPT1/2 embedded in mitochondrion membrane actively transported melatonin into mitochondrion and consequently induced apoptotic pathway. Hevia et al. [152] demonstrated melatonin can limit glycolysis as well as the tricarboxylic acid (TCA) cycle and pentose phosphate pathway in PCa cells. By conducting a 13C stable isotope-resolved metabolomic study, they found melatonin could significantly decrease glucose uptake, ATP production, LDH activity and almost all of the intermediates of the TCA cycle. The results implied a general negative effect of melatonin on glucose uptake and utilization in PCa cells (Fig. 3). Dauchy et al. [59] showed that mice bred in blue-tinted rodent cages have an elevated melatonin level in circulation, which inhibited the metabolism rate and growth of PCa xenografts.

Fig. 3

Inhibition of melatonin on PCa metabolism. Melatonin can be actively transported into PCa cells via GLUT1 and thus suppressing the uptake of glucose via competing for the binding sites of GLUT1. PEPT1/2 embedded in mitochondrion membrane actively transported melatonin into mitochondrion. Melatonin can cause 10–20% decrease in ATP production via limiting the TCA cycle and cause roughly 15% decrease of lactate via inhibiting glycolysis

PCa angiogenesis and neuroendocrine differentiation

Angiogenesis is an essential physiological process that occurs in tissue healing and embryonic development. Cancerous neovascular vessels build a bridge between tumor tissues and the pre-existing tissues. The newly sprouted vessels help exchange wastes and nutrients between tumor and human body and provide a new route for tumor cells to migrate and renew [36, 153]. Thus, angiogenesis is critical for tumor progression [154] and is regarded as a new hallmark of cancers [155]. For PCa, although there are no convincing markers to evaluate the angiogenic rate, intratumoral microvessel density (MVD) is recognized as a good biomarker. Detection of contrast-enhanced ultrasonography also confirmed a higher signal intensity of blood flow in advanced PCa patients [156]. Patients with higher MVD tended to show higher Gleason scores and worse prognosis [157, 158].

The initiation of angiogenesis can be seen as an imbalance between angiogenesis inducing factors and angiogenesis inhibitory factors that favor the former group. Vascular endothelial growth factor (VEGF), an extensively studied inducer, is confirmed to be associated with PCa angiogenesis. Previous studies showed that the expression level of VEGF-A, a VEGF isoform, is up-regulated in PCa and is correlated with distant metastasis and overall prognosis [159, 160]. It is noteworthy that androgen and AR participate in angiogenesis partially via regulating VEGF and its upstream regulators [161]. For instance, HIF-1α, a well-established modulator of VEGF, is demonstrated to be activated by DHT [162, 163]. Interestingly, castration treatment can decrease the oxygen content in the microenvironment [164, 165]. While the low-oxygen environment activates HIF-1α to enhance the transcription of AR in PCa cells [166].

A preliminary clinical study demonstrated that patients who accepted melatonin treatment showed decreased serum levels of VEGF, showing the potential anti-angiogenic activity of melatonin [167]. Several studies have also pointed out that melatonin can inhibit tumor growth by blocking the development of neovascularization [167,168,169,170].

The pharmacologic concentration of melatonin (1 mM) is confirmed to inhibit the translation of HIF-1α protein while not decreasing its protein stability or mRNA transcription and the inhibition of HIF-1α consequently leading to the down-expression of VEGF-A in PCa cells [171]. Interestingly, the physiological concentration of melatonin (1 nM) fails to show the identical ability compared to the high concentration. Cho et al. [172] further reported an SHPK1-mediated regulation of melatonin on HIF-1α. Sphingosine kinase 1 (SHPK1) is a known HIF-1α regulator via maintaining HIF-1α stability [173] and melatonin at 1 mm dramatically reduced SPHK1 expression as well as HIF-1α and VEGF in hypoxic PC-3 cells. MicroRNA is a kind of noncoding RNA containing about 22 nucleotides. MicroRNA inhibited gene expression through sequence-specific interaction with the untranslated region (UTR) of homologous mRNA [174, 175] and melatonin was proved to regulate microRNA to inhibit tumor angiogenesis. Sohn et al. [176] reported that treating hypoxic PC-3 cells with melatonin could up-regulate the expression of miRNA3195 and miRNA374b. MiRNA3195 and miRNA374b, in turn, restrain the level of HIF-1α and VEGF at a transcriptional level and thus inhibited the angiogenesis and migration abilities of PCa cells.

Neuroendocrine differentiation (NED) is a commonly observed phenotypic change during ADT. NED cells are characterized by the expression of NE markers, including NSE, CgA, gastrin, and neurotensin [177]. This phenotype change is believed to be correlated with tumor progression, poor prognosis, and hormone-refractory. Typically, three main methods are leading to the NED [178], (1) Androgen depletion-induced NED [179, 180], (2) cAMP-induced NED [181, 182], (3) Cytokines-induced NED [183, 184]. Other agents such as HB-EGF [185] or Vasoactive intestinal peptide (VIP) [186] are also reported to mediate the progression of NED.

Interestingly, although NED seems to be a negative factor of PCa, melatonin still can induce this transformation without damaging its anti-proliferation effects [187]. Sainz et al. [188] reported that after being cultured with melatonin for six days, cells began to exhibit the NED characteristics and express a high level of NSE via an MT1-independent and PKA-independent pathway since the elevation of the cAMP level is transient. Mayo et al. [189] demonstrated a further underlying mechanism that involves activated MAPK/ERK 1/2 pathway, redox regulation and androgen receptor nuclear exclusion. Melatonin treatment not only increased the intracellular GSH level but also enhancing the ADT-dependent NED. And genomic microarray showed that IGFBP3 is the key gene that regulates the NED process of melatonin. In addition, Rodriguez-Garcia et al. [190] confirmed that NED does not increase survival chances for PCa cells. On the contrary, melatonin-induced NED may be responsible for greater sensitivity to cytokines, namely TNFα and TRAIL.

According to Wang et al. [191], there is a potential correlation between PCa angiogenesis and NED. Previous studies pointed out that PCa specimens with a high degree of NED also have more neovascularization and VEGF staining [192]. Moreover, although being reported in separate diseases or biological contexts, proteins, such as CHGA, p53 and HIF-1α, that regulate angiogenesis also participate in the progress of NED [191]. While as we have discussed that melatonin can inhibit angiogenesis and promote NED, there seems to be a contradiction in the effect of melatonin on PCa. Thus, we speculate that the transformation of NED is an incidental effect of melatonin on increasing cell sensitivity to cytokines treatment, and the inhibitory effect on angiogenesis is the more important one. Of course, more specific mechanisms of this contradiction remain to be studied.

Melatonin and apoptosis of prostate cancer cells

Apoptosis, a genetically programmed cell death, is highly conserved among many species [193]. Moderately activated apoptosis helps to clear unwanted cells such as dead white blood cells in immune responses or cells with harmful mutations caused by external stimuli [194, 195]. The balance between cell growth, dormancy, apoptosis is of great importance to maintain homeostasis while dysregulation of this harmonious relationship is an underlying mechanism of tumorigenesis and is also regarded as a hallmark of cancers [155, 196, 197]. The well-accepted apoptotic features include cell contraction, chromatin aggregation, and DNA ladder formation caused by internucleosomal DNA fragmentation, which ends with phagocytosis by macrophages or adjacent cells, thus avoiding inflammatory reactions among surrounding tissues [198].

As a nature oncostatic hormone, the ability of melatonin to promote cell death is validated in many types of cancers [199], and similar outcomes are also found in PCa. Joo et al. [200] showed that treating the androgen-sensitive LNCaP cells with melatonin clearly increased the number of apoptotic cells with a significant up-regulation of apoptosis-related proteins Bax and Cyt c and a decrease of survival protein Bcl-2, via activating the JNK and p38 cascade. Sainz et al. [201] examined the effect of melatonin when given in combination with TNFα or γ-radiation. Results showed that melatonin obviously arrests PCa cells in the G0/G1 phase with an increase of p21 protein and significantly elevates the efficiency of TNFα treatment via inactivating NF-κB. However, melatonin failed to enhance the apoptosis induced by γ-radiation due to the increment of intracellular glutathione. Rodriguez-Garcia et al. [190] further investigated whether melatonin could promote drug-induced apoptosis combined with doxorubicin, docetaxel, and etoposide or cytokines like TNFα and TRAIL. Interestingly, results showed that melatonin exclusively promoted cell toxicity caused by cytokines but did not appear to promote the efficiency of other chemotherapeutic drugs.

The synergistic interactions of melatonin and other drugs

Melatonin is an endogenous oncostatic agent that displays almost null toxicity to human body [202, 203]. The synergistic interactions of melatonin and other drugs are found to achieve an ideal therapeutic effect and reduce side-effects [204,205,206]. The similar anti-proliferative effect of melatonin and other anticarcinogens present on human tumors in vivo and in vitro abstracts researchers to make further investigation.

As Reiter et al. reported, proper use of melatonin combined with other oncostatic agents can enhance the therapeutic effect [207]. For instance, DHA, a fatty acid present in the human diet, can exert a pro-apoptotic effect against PCa cells via Akt-mTOR signaling. In an in vitro study, Tamarindo et al. [208] found that melatonin combined with DHA could suppress proliferative prostate diseases through modulating mitochondrion bioenergy via AKT and ERK1/2 pathway. In another animal model research, Terraneo et al. [209] reported that they developed a noninvasive and painless therapy for PCa which combined melatonin and cryopass-laser treatment. Via cryopass-laser, melatonin could be precisely delivered to specific areas avoiding false distribution in non-target tissues and unwanted side-effects. 3 mg/kg/week melatonin (0.09 mg/mouse/week) delivered by i.p. injections could effectively inhibit the proliferation of LNCaP PCa cells. This study brought a bright future for devising alternative ways to deliver melatonin in clinical contexts.


Prostate cancer (PCa) is one of the most common cancers among male patients. In 2020, nearly 191,930 new cases and 33,330 deaths of PCa are estimated with a constantly rising trend. Melatonin (N-acetyl-methoxy-tryptamine), an indole-like neurohormone, is synthesized and secreted from the pineal gland. Melatonin is mainly produced in a dark condition while light could inhibit the internal synthesis. Melatonin could exert multiple biological effects, especially as a free radical scavenger. Recently, melatonin emerges as a prospective therapeutic agent with a series of beneficial effects on human cancers over a wide range of concentrations and tumor types. In this review article, we predominantly discuss the anti-tumor effects of melatonin on human PCa. The underlying mechanisms of how melatonin inhibits the growth and progression of PCa were related to the promotion of AR exclusion, activation of MT1 signaling, modulation of PCa metabolism, inhibition of angiogenesis, regulation of neuroendocrine differentiation, induction of apoptosis. Moreover, melatonin also exerts synergistic benefits while incorporating with other chemotherapeutic agents and is an effective adjuvant to androgen depletion therapy. Melatonin is also hopeful to be a noninvasive biomarker for predicting PCa since a low urinary melatonin level is highly correlated to the incidence of PCa. Although substantial evidence suggests that melatonin could be a novel strategy for the treatment of PCa, compared with the well-explored relationship between melatonin and breast cancer, further clarification of the melatonin-mediated inhibitory effects on PCa deserves more attention. It is clear that several unsolved issues need to be resolved. For instance, only a few surveys were conducted in a clinical situation while the majority of the above findings remain in the phase of in vivo and in vitro experiments. More efforts need to be spared to translate currently non-clinical trials of melatonin to clinic use. All in all, we hope data compiled in this review will help promote the utilization of melatonin in overcoming human prostate cancer.

Availability of data and materials

Not applicable.





Androgen depletion therapy


Artificial light at night


Androgen receptor


Benign prostatic hyperplasia


Castration resistant prostate cancer




Docosahexaenoic acid




Fluorodeoxyglucose positron emission tomography




Prostate cancer


Protein kinase A


Protein kinase C


Phospholipase C


Phospholipase D


Prostate specific antigens


Regulators of G-protein signaling


Reactive nitrogen species


Retinoic acid-related orphan receptor


Reactive oxygen species


Retinoid Z receptor


Transgenic adenocarcinoma of a mouse prostate


  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.

    PubMed  Article  Google Scholar 

  3. 3.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.

    PubMed  Article  Google Scholar 

  4. 4.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.

    Article  Google Scholar 

  5. 5.

    De Maeseneer DJ, Van Praet C, Lumen N, Rottey S. Battling resistance mechanisms in antihormonal prostate cancer treatment: Novel agents and combinations. Urol Oncol. 2015;33:310–21.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Saranyutanon S, Srivastava SK, Pai S, Singh S, Singh AP. Therapies targeted to androgen receptor signaling axis in prostate cancer: progress, challenges, and hope. Cancers (Basel). 2019;12:51.

    Article  CAS  Google Scholar 

  7. 7.

    Cai C, Chen S, Ng P, Bubley GJ, Nelson PS, Mostaghel EA, Marck B, Matsumoto AM, Simon NI, Wang H, et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res. 2011;71:6503–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Beltran H, Wyatt AW, Chedgy EC, Donoghue A, Annala M, Warner EW, Beja K, Sigouros M, Mo F, Fazli L, et al. Impact of therapy on genomics and transcriptomics in high-risk prostate cancer treated with neoadjuvant docetaxel and androgen deprivation therapy. Clin Cancer Res. 2017;23:6802–11.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Wong SK, Mohamad NV, Giaze TR, Chin KY, Mohamed N, Ima-Nirwana S. Prostate cancer and bone metastases: the underlying mechanisms. Int J Mol Sci. 2019;20:2587.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  10. 10.

    Carvalho-Sousa CE, Pereira EP, Kinker GS, Veras M, Ferreira ZS, Barbosa-Nunes FP, Martins JO, Saldiva PHN, Reiter RJ, Fernandes PA, et al. Immune-pineal axis protects rat lungs exposed to polluted air. J Pineal Res. 2020;68:e12636.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Acuna-Castroviejo D, Escames G, Venegas C, Diaz-Casado ME, Lima-Cabello E, Lopez LC, Rosales-Corral S, Tan DX, Reiter RJ. Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci. 2014;71:2997–3025.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Alkozi HA, Wang X, Perez de Lara MJ, Pintor J. Presence of melanopsin in human crystalline lens epithelial cells and its role in melatonin synthesis. Exp Eye Res. 2017;154:168–76.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Sanchez-Hidalgo M, de la Lastra CA, Carrascosa-Salmoral MP, Naranjo MC, Gomez-Corvera A, Caballero B, Guerrero JM. Age-related changes in melatonin synthesis in rat extrapineal tissues. Exp Gerontol. 2009;44:328–34.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Soderquist F, Hellstrom PM, Cunningham JL. Human gastroenteropancreatic expression of melatonin and its receptors MT1 and MT2. PLoS ONE. 2015;10:e0120195.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. 15.

    Stehle JH, Saade A, Rawashdeh O, Ackermann K, Jilg A, Sebesteny T, Maronde E. A survey of molecular details in the human pineal gland in the light of phylogeny, structure, function and chronobiological diseases. J Pineal Res. 2011;51:17–43.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Reiter RJ. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev. 1991;12:151–80.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Dominguez-Rodriguez A, Abreu-Gonzalez P, Reiter RJ. Clinical aspects of melatonin in the acute coronary syndrome. Curr Vasc Pharmacol. 2009;7:367–73.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Chattoraj A, Liu T, Zhang LS, Huang Z, Borjigin J. Melatonin formation in mammals: in vivo perspectives. Rev Endocr Metab Disord. 2009;10:237–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Giudice A, Crispo A, Grimaldi M, Polo A, Bimonte S, Capunzo M, Amore A, D’Arena G, Cerino P, Budillon A, et al. The effect of light exposure at night (LAN) on carcinogenesis via decreased nocturnal melatonin synthesis. Molecules. 2018;23:1308.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  20. 20.

    Schilperoort M, van den Berg R, Bosmans LA, van Os BW, Dolle MET, Smits NAM, Guichelaar T, van Baarle D, Koemans L, Berbee JFP, et al. Disruption of circadian rhythm by alternating light-dark cycles aggravates atherosclerosis development in APOE*3-Leiden.CETP mice. J Pineal Res. 2020;68:e12614.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Galano A, Reiter RJ. Melatonin and its metabolites vs oxidative stress: From individual actions to collective protection. J Pineal Res. 2018;65:e12514.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Manchester LC, Coto-Montes A, Boga JA, Andersen LP, Zhou Z, Galano A, Vriend J, Tan DX, Reiter RJ. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res. 2015;59:403–19.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res. 2016;61:253–78.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    de Almeida Chuffa LG, Seiva FRF, Cucielo MS, Silveira HS, Reiter RJ, Lupi LA. Mitochondrial functions and melatonin: a tour of the reproductive cancers. Cell Mol Life Sci. 2019;76:837–63.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Niu YJ, Zhou W, Nie ZW, Shin KT, Cui XS. Melatonin enhances mitochondrial biogenesis and protects against rotenone-induced mitochondrial deficiency in early porcine embryos. J Pineal Res. 2020;68:e12627.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Sun C, Lv T, Huang L, Liu X, Jin C, Lin X. Melatonin ameliorates aluminum toxicity through enhancing aluminum exclusion and reestablishing redox homeostasis in roots of wheat. J Pineal Res. 2020;68:e12642.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Tan DX, Manchester LC, Liu X, Rosales-Corral SA, Acuna-Castroviejo D, Reiter RJ. Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin’s primary function and evolution in eukaryotes. J Pineal Res. 2013;54:127–38.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Cipolla-Neto J, Amaral FG, Afeche SC, Tan DX, Reiter RJ. Melatonin, energy metabolism, and obesity: a review. J Pineal Res. 2014;56:371–81.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Gonzalez-Candia A, Candia AA, Figueroa EG, Feixes E, Gonzalez-Candia C, Aguilar SA, Ebensperger G, Reyes RV, Llanos AJ, Herrera EA. Melatonin long-lasting beneficial effects on pulmonary vascular reactivity and redox balance in chronic hypoxic ovine neonates. J Pineal Res. 2020;68:e12613.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Leem J, Bai GY, Kim JS, Oh JS. Melatonin protects mouse oocytes from DNA damage by enhancing nonhomologous end-joining repair. J Pineal Res. 2019;67:e12603.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Ma Z, Liu D, Di S, Zhang Z, Li W, Zhang J, Xu L, Guo K, Zhu Y, Li X, et al. Histone deacetylase 9 downregulation decreases tumor growth and promotes apoptosis in non-small cell lung cancer after melatonin treatment. J Pineal Res. 2019;67:e12587.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Boga JA, Caballero B, Potes Y, Perez-Martinez Z, Reiter RJ, Vega-Naredo I, Coto-Montes A. Therapeutic potential of melatonin related to its role as an autophagy regulator: a review. J Pineal Res. 2019;66:e12534.

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Qian Y, Han Q, Zhao X, Song J, Cheng Y, Fang Z, Ouyang Y, Yuan WE, Fan C. 3D melatonin nerve scaffold reduces oxidative stress and inflammation and increases autophagy in peripheral nerve regeneration. J Pineal Res. 2018;65:e12516.

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Tian T, Li J, Li Y, Lu YX, Tang YL, Wang H, Zheng F, Shi D, Long Q, Chen M, et al. Melatonin enhances sorafenib-induced cytotoxicity in FLT3-ITD acute myeloid leukemia cells by redox modification. Theranostics. 2019;9:3768–79.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Ju HQ, Li H, Tian T, Lu YX, Bai L, Chen LZ, Sheng H, Mo HY, Zeng JB, Deng W, et al. Melatonin overcomes gemcitabine resistance in pancreatic ductal adenocarcinoma by abrogating nuclear factor-kappaB activation. J Pineal Res. 2016;60:27–38.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Su SC, Hsieh MJ, Yang WE, Chung WH, Reiter RJ, Yang SF. Cancer metastasis: mechanisms of inhibition by melatonin. J Pineal Res. 2017;62:e12394.

    Article  CAS  Google Scholar 

  37. 37.

    Karunanithi D, Radhakrishna A, Sivaraman KP, Biju VM. Quantitative determination of melatonin in milk by LC-MS/MS. J Food Sci Technol. 2014;51:805–12.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Asher A, Shabtay A, Brosh A, Eitam H, Agmon R, Cohen-Zinder M, Zubidat AE, Haim A. “Chrono-functional milk”: the difference between melatonin concentrations in night-milk versus day-milk under different night illumination conditions. Chronobiol Int. 2015;32:1409–16.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Milagres MP, Minim VP, Minim LA, Simiqueli AA, Moraes LE, Martino HS. Night milking adds value to cow’s milk. J Sci Food Agric. 2014;94:1688–92.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Salehi B, Sharopov F, Fokou PVT, Kobylinska A, Jonge L, Tadio K, Sharifi-Rad J, Posmyk MM, Martorell M, Martins N, Iriti M. Melatonin in medicinal and food plants: occurrence, bioavailability, and health potential for humans. Cells. 2019;8:681.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  41. 41.

    Sae-Teaw M, Johns J, Johns NP, Subongkot S. Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers. J Pineal Res. 2013;55:58–64.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Chen G, Huo Y, Tan DX, Liang Z, Zhang W, Zhang Y. Melatonin in Chinese medicinal herbs. Life Sci. 2003;73:19–26.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Anisimov VN, Vinogradova IA, Panchenko AV, Popovich IG, Zabezhinski MA. Light-at-night-induced circadian disruption, cancer and aging. Curr Aging Sci. 2012;5:170–7.

    PubMed  Article  Google Scholar 

  44. 44.

    Kubo T, Ozasa K, Mikami K, Wakai K, Fujino Y, Watanabe Y, Miki T, Nakao M, Hayashi K, Suzuki K, et al. Prospective cohort study of the risk of prostate cancer among rotating-shift workers: findings from the Japan collaborative cohort study. Am J Epidemiol. 2006;164:549–55.

    PubMed  Article  Google Scholar 

  45. 45.

    Papantoniou K, Castano-Vinyals G, Espinosa A, Turner MC, Alonso-Aguado MH, Martin V, Aragones N, Perez-Gomez B, Pozo BM, Gomez-Acebo I, et al. Shift work and colorectal cancer risk in the MCC-Spain case-control study. Scand J Work Environ Health. 2017;43:250–9.

    PubMed  Article  Google Scholar 

  46. 46.

    Sigurdardottir LG, Markt SC, Rider JR, Haneuse S, Fall K, Schernhammer ES, Tamimi RM, Flynn-Evans E, Batista JL, Launer L, et al. Urinary melatonin levels, sleep disruption, and risk of prostate cancer in elderly men. Eur Urol. 2015;67:191–4.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Xin Z, Jiang S, Jiang P, Yan X, Fan C, Di S, Wu G, Yang Y, Reiter RJ, Ji G. Melatonin as a treatment for gastrointestinal cancer: a review. J Pineal Res. 2015;58:375–87.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Feychting M, Osterlund B, Ahlbom A. Reduced cancer incidence among the blind. Epidemiology. 1998;9:490–4.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Flynn-Evans EE, Stevens RG, Tabandeh H, Schernhammer ES, Lockley SW. Total visual blindness is protective against breast cancer. Cancer Causes Control. 2009;20:1753–6.

    PubMed  Article  Google Scholar 

  50. 50.

    Hahn RA. Does blindness protect against cancers? Epidemiology. 1998;9:481–3.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Kliukiene J, Tynes T, Andersen A. Risk of breast cancer among Norwegian women with visual impairment. Br J Cancer. 2001;84:397–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Straif K, Baan R, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, Altieri A, Benbrahim-Tallaa L, Cogliano V, WHOIAFRoCMW Group. Carcinogenicity of shift-work, painting, and fire-fighting. Lancet Oncol. 2007;8:1065–6.

    PubMed  Article  Google Scholar 

  53. 53.

    Bartsch C, Bartsch H, Fluchter SH, Attanasio A, Gupta D. Evidence for modulation of melatonin secretion in men with benign and malignant tumors of the prostate: relationship with the pituitary hormones. J Pineal Res. 1985;2:121–32.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Papantoniou K, Castano-Vinyals G, Espinosa A, Aragones N, Perez-Gomez B, Burgos J, Gomez-Acebo I, Llorca J, Peiro R, Jimenez-Moleon JJ, et al. Night shift work, chronotype and prostate cancer risk in the MCC-Spain case-control study. Int J Cancer. 2015;137:1147–57.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Wendeu-Foyet MG, Bayon V, Cenee S, Tretarre B, Rebillard X, Cancel-Tassin G, Cussenot O, Lamy PJ, Faraut B, Ben Khedher S, et al. Night work and prostate cancer risk: results from the EPICAP study. Occup Environ Med. 2018;75:573–81.

    PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Tai SY, Huang SP, Bao BY, Wu MT. Urinary melatonin-sulfate/cortisol ratio and the presence of prostate cancer: a case-control study. Sci Rep. 2016;6:29606.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Kim KY, Lee E, Kim YJ, Kim J. The association between artificial light at night and prostate cancer in Gwangju City and South Jeolla Province of South Korea. Chronobiol Int. 2017;34:203–11.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Blask DE, Dauchy RT, Dauchy EM, Mao L, Hill SM, Greene MW, Belancio VP, Sauer LA, Davidson L. Light exposure at night disrupts host/cancer circadian regulatory dynamics: impact on the Warburg effect, lipid signaling and tumor growth prevention. PLoS ONE. 2014;9:e102776.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  59. 59.

    Dauchy RT, Hoffman AE, Wren-Dail MA, Hanifin JP, Warfield B, Brainard GC, Xiang S, Yuan L, Hill SM, Belancio VP, et al. Daytime blue light enhances the nighttime circadian melatonin inhibition of human prostate cancer growth. Comp Med. 2015;65:473–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Graff RE, Kachuri L, Witte JS. Personalized prostate cancer screening based on a single midlife prostate-specific antigen measurement. Eur Urol. 2019;75:408–9.

    PubMed  Article  Google Scholar 

  61. 61.

    Heemers HV. Targeting androgen receptor action for prostate cancer treatment: does the post-receptor level provide novel opportunities? Int J Biol Sci. 2014;10:576–87.

    PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    La Vignera S, Condorelli RA, Russo GI, Morgia G, Calogero AE. Endocrine control of benign prostatic hyperplasia. Andrology. 2016;4:404–11.

    PubMed  Article  CAS  Google Scholar 

  63. 63.

    Phillips R. Prostate cancer: novel targeting of androgen signalling in CRPC. Nat Rev Urol. 2014;11:303.

    PubMed  Article  Google Scholar 

  64. 64.

    Labrie F, Belanger A, Luu-The V, Labrie C, Simard J, Cusan L, Gomez J, Candas B. Gonadotropin-releasing hormone agonists in the treatment of prostate cancer. Endocr Rev. 2005;26:361–79.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Labrie F, Cusan L, Gomez JL, Martel C, Berube R, Belanger P, Belanger A, Vandenput L, Mellstrom D, Ohlsson C. Comparable amounts of sex steroids are made outside the gonads in men and women: strong lesson for hormone therapy of prostate and breast cancer. J Steroid Biochem Mol Biol. 2009;113:52–6.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Labrie F, Dupont A, Belanger A. Complete androgen blockade for the treatment of prostate cancer. Important Adv Oncol. 1985;55:193–217.

    Google Scholar 

  67. 67.

    Husmann DA, Wilson CM, McPhaul MJ, Tilley WD, Wilson JD. Antipeptide antibodies to two distinct regions of the androgen receptor localize the receptor protein to the nuclei of target cells in the rat and human prostate. Endocrinology. 1990;126:2359–68.

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Sar M, Lubahn DB, French FS, Wilson EM. Immunohistochemical localization of the androgen receptor in rat and human tissues. Endocrinology. 1990;127:3180–6.

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Heery DM, Kalkhoven E, Hoare S, Parker MG. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature. 1997;387:733–6.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Suzuki H, Sato N, Watabe Y, Masai M, Seino S, Shimazaki J. Androgen receptor gene mutations in human prostate cancer. J Steroid Biochem Mol Biol. 1993;46:759–65.

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Steketee K, Timmerman L, Ziel-van der Made AC, Doesburg P, Brinkmann AO, Trapman J. Broadened ligand responsiveness of androgen receptor mutants obtained by random amino acid substitution of H874 and mutation hot spot T877 in prostate cancer. Int J Cancer. 2002;100:309–17.

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    van de Wijngaart DJ, Molier M, Lusher SJ, Hersmus R, Jenster G, Trapman J, Dubbink HJ. Systematic structure-function analysis of androgen receptor Leu701 mutants explains the properties of the prostate cancer mutant L701H. J Biol Chem. 2010;285:5097–105.

    PubMed  Article  CAS  Google Scholar 

  73. 73.

    Lallous N, Volik SV, Awrey S, Leblanc E, Tse R, Murillo J, Singh K, Azad AA, Wyatt AW, LeBihan S, et al. Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients. Genome Biol. 2016;17:10.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer. 2015;15:701–11.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Labrie F, Belanger A, Belanger P, Berube R, Martel C, Cusan L, Gomez J, Candas B, Castiel I, Chaussade V, et al. Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women. J Steroid Biochem Mol Biol. 2006;99:182–8.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Kawata H, Ishikura N, Watanabe M, Nishimoto A, Tsunenari T, Aoki Y. Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity. Prostate. 2010;70:745–54.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Carreira S, Romanel A, Goodall J, Grist E, Ferraldeschi R, Miranda S, Prandi D, Lorente D, Frenel JS, Pezaro C, et al. Tumor clone dynamics in lethal prostate cancer. Sci Transl Med. 2014;6:254ra125.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. 78.

    Antonarakis ES, Armstrong AJ, Dehm SM, Luo J. Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting. Prostate Cancer Prostatic Dis. 2016;19:231–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Luo J. Development of AR-V7 as a putative treatment selection marker for metastatic castration-resistant prostate cancer. Asian J Androl. 2016;18:580–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Luo J, Attard G, Balk SP, Bevan C, Burnstein K, Cato L, Cherkasov A, De Bono JS, Dong Y, Gao AC, et al. Role of androgen receptor variants in prostate cancer: report from the 2017 mission androgen receptor variants meeting. Eur Urol. 2018;73:715–23.

    PubMed  Article  Google Scholar 

  81. 81.

    Molis TM, Spriggs LL, Jupiter Y, Hill SM. Melatonin modulation of estrogen-regulated proteins, growth factors, and proto-oncogenes in human breast cancer. J Pineal Res. 1995;18:93–103.

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    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;13:857–68.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Nazareth LV, Stenoien DL, Bingman WE 3rd, James AJ, Wu C, Zhang Y, Edwards DP, Mancini M, Marcelli M, Lamb DJ, Weigel NL. A C619Y mutation in the human androgen receptor causes inactivation and mislocalization of the receptor with concomitant sequestration of SRC-1 (steroid receptor coactivator 1). Mol Endocrinol. 1999;13:2065–75.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Kobayashi Y, Kume A, Li M, Doyu M, Hata M, Ohtsuka K, Sobue G. Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract. J Biol Chem. 2000;275:8772–8.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Ross CA. Intranuclear neuronal inclusions: a common pathogenic mechanism for glutamine-repeat neurodegenerative diseases? Neuron. 1997;19:1147–50.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Rimler A, Culig Z, Levy-Rimler G, Lupowitz Z, Klocker H, Matzkin H, Bartsch G, Zisapel N. Melatonin elicits nuclear exclusion of the human androgen receptor and attenuates its activity. Prostate. 2001;49:145–54.

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Rimler A, Culig Z, Lupowitz Z, Zisapel N. Nuclear exclusion of the androgen receptor by melatonin. J Steroid Biochem Mol Biol. 2002;81:77–84.

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    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):45–9.

    CAS  PubMed  Google Scholar 

  89. 89.

    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;58:2129–35.

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Rimler A, Jockers R, Lupowitz Z, Zisapel N. Gi and RGS proteins provide biochemical control of androgen receptor nuclear exclusion. J Mol Neurosci. 2007;31:1–12.

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Gomella LG. Effective testosterone suppression for prostate cancer: is there a best castration therapy? Rev Urol. 2009;11:52–60.

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Hellerstedt BA, Pienta KJ. The current state of hormonal therapy for prostate cancer. CA Cancer J Clin. 2002;52:154–79.

    PubMed  Article  Google Scholar 

  93. 93.

    Wu JN, Fish KM, Evans CP, Devere White RW, Dall’Era MA. No improvement noted in overall or cause-specific survival for men presenting with metastatic prostate cancer over a 20-year period. Cancer. 2014;120:818–23.

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Holzbeierlein J, Lal P, LaTulippe E, Smith A, Satagopan J, Zhang L, Ryan C, Smith S, Scher H, Scardino P, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol. 2004;164:217–27.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Mousses S, Wagner U, Chen Y, Kim JW, Bubendorf L, Bittner M, Pretlow T, Elkahloun AG, Trepel JB, Kallioniemi OP. Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling. Oncogene. 2001;20:6718–23.

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33–9.

    PubMed  Article  CAS  Google Scholar 

  97. 97.

    Cheng H, Snoek R, Ghaidi F, Cox ME, Rennie PS. Short hairpin RNA knockdown of the androgen receptor attenuates ligand-independent activation and delays tumor progression. Cancer Res. 2006;66:10613–20.

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Snoek R, Cheng H, Margiotti K, Wafa LA, Wong CA, Wong EC, Fazli L, Nelson CC, Gleave ME, Rennie PS. In vivo knockdown of the androgen receptor results in growth inhibition and regression of well-established, castration-resistant prostate tumors. Clin Cancer Res. 2009;15:39–47.

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Zegarra-Moro OL, Schmidt LJ, Huang H, Tindall DJ. Disruption of androgen receptor function inhibits proliferation of androgen-refractory prostate cancer cells. Cancer Res. 2002;62:1008–13.

    CAS  PubMed  Google Scholar 

  100. 100.

    Zong Y, Goldstein AS. Adaptation or selection—mechanisms of castration-resistant prostate cancer. Nat Rev Urol. 2013;10:90–8.

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Siu SW, Lau KW, Tam PC, Shiu SY. Melatonin and prostate cancer cell proliferation: interplay with castration, epidermal growth factor, and androgen sensitivity. Prostate. 2002;52:106–22.

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Xi SC, Tam PC, Brown GM, Pang SF, Shiu SY. 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;29:172–83.

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Xi SC, Siu SW, Fong SW, Shiu SY. 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;46:52–61.

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Liu VWS, Yau WL, Tam CW, Yao KM, Shiu SYW. Melatonin inhibits androgen receptor splice variant-7 (AR-V7)-induced nuclear factor-kappa B (NF-kappaB) activation and NF-kappaB activator-induced AR-V7 expression in prostate cancer cells: potential implications for the use of melatonin in castration-resistant prostate cancer (CRPC) therapy. Int J Mol Sci. 2017;18:1130.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  105. 105.

    Lissoni P, Cazzaniga M, Tancini G, Scardino E, Musci R, Barni S, Maffezzini M, Meroni T, Rocco F, Conti A, Maestroni G. Reversal of clinical resistance to LHRH analogue in metastatic prostate cancer by the pineal hormone melatonin: efficacy of LHRH analogue plus melatonin in patients progressing on LHRH analogue alone. Eur Urol. 1997;31:178–81.

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Zharinov GM, Bogomolov OA, Chepurnaya IV, Neklasova NY, Anisimov VN. Melatonin increases overall survival of prostate cancer patients with poor prognosis after combined hormone radiation treatment. Oncotarget. 2020;11:3723–9.

    PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Galsky MD, Small AC, Tsao CK, Oh WK. Clinical development of novel therapeutics for castration-resistant prostate cancer: historic challenges and recent successes. CA Cancer J Clin. 2012;62:299–308.

    PubMed  Article  Google Scholar 

  108. 108.

    Cui K, Li X, Du Y, Tang X, Arai S, Geng Y, Xi Y, Xu H, Zhou Y, Ma W, Zhang T. Chemoprevention of prostate cancer in men with high-grade prostatic intraepithelial neoplasia (HGPIN): a systematic review and adjusted indirect treatment comparison. Oncotarget. 2017;8:36674–84.

    PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65:1180–92.

    CAS  Article  Google Scholar 

  110. 110.

    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 USA. 1995;92:8734–8.

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Reppert SM, Tsai T, Roca AL, Sauman I. Cloning of a structural and functional homolog of the circadian clock gene period from the giant silkmoth Antheraea pernyi. Neuron. 1994;13:1167–76.

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Reppert SM, Weaver DR, Ebisawa T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron. 1994;13:1177–85.

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Cecon E, Liu L, Jockers R. Melatonin receptor structures shed new light on melatonin research. J Pineal Res. 2019;67:e12606.

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Cecon E, Oishi A, Jockers R. Melatonin receptors: molecular pharmacology and signalling in the context of system bias. Br J Pharmacol. 2018;175:3263–80.

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Winczyk K, Pawlikowski M, Karasek M. Melatonin and RZR/ROR receptor ligand CGP 52608 induce apoptosis in the murine colonic cancer. J Pineal Res. 2001;31:179–82.

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Winczyk K, Pawlikowski M, Lawnicka H, Kunert-Radek J, Spadoni G, Tarzia G, Karasek M. Effects of melatonin and melatonin receptors ligand N-[(4-methoxy-1H-indol-2-yl)methyl]propanamide on murine Colon 38 cancer growth in vitro and in vivo. Neuro Endocrinol Lett. 2002;23(Suppl 1):50–4.

    CAS  PubMed  Google Scholar 

  117. 117.

    Nasrabadi NN, Ataee R, Abediankenari S, Shokrzadeh M, Najafi M, Hoseini SV, Jan HH. Expression of MT2 receptor in patients with gastric adenocarcinoma and its relationship with clinicopathological features. J Gastrointest Cancer. 2014;45:54–60.

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Dillon DC, Easley SE, Asch BB, Cheney RT, Brydon L, Jockers R, Winston JS, Brooks JS, Hurd T, Asch HL. Differential expression of high-affinity melatonin receptors (MT1) in normal and malignant human breast tissue. Am J Clin Pathol. 2002;118:451–8.

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Ram PT, Dai J, Yuan L, Dong C, Kiefer TL, Lai L, Hill SM. Involvement of the mt1 melatonin receptor in human breast cancer. Cancer Lett. 2002;179:141–50.

    CAS  PubMed  Article  Google Scholar 

  120. 120.

    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;35:177–82.

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Revandkar A, Perciato ML, Toso A, Alajati A, Chen J, Gerber H, Dimitrov M, Rinaldi A, Delaleu N, Pasquini E, et al. Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence. Nat Commun. 2016;7:13719.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Roy S, Gu M, Ramasamy K, Singh RP, Agarwal C, Siriwardana S, Sclafani RA, Agarwal R. p21/Cip1 and p27/Kip1 Are essential molecular targets of inositol hexaphosphate for its antitumor efficacy against prostate cancer. Cancer Res. 2009;69:1166–73.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    De Marzo AM, Marchi VL, Epstein JI, Nelson WG. Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am J Pathol. 1999;155:1985–92.

    PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Lloyd RV, Erickson LA, Jin L, Kulig E, Qian X, Cheville JC, Scheithauer BW. p27kip1: a multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. Am J Pathol. 1999;154:313–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Shiu SY, Leung WY, Tam CW, Liu VW, Yao KM. Melatonin MT1 receptor-induced transcriptional up-regulation of p27(Kip1) in prostate cancer antiproliferation is mediated via inhibition of constitutively active nuclear factor kappa B (NF-kappaB): potential implications on prostate cancer chemoprevention and therapy. J Pineal Res. 2013;54:69–79.

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    Shiu SY, Pang B, Tam CW, Yao KM. Signal transduction of receptor-mediated antiproliferative action of melatonin on human prostate epithelial cells involves dual activation of Galpha(s) and Galpha(q) proteins. J Pineal Res. 2010;49:301–11.

    CAS  PubMed  Article  Google Scholar 

  127. 127.

    Tam CW, Mo CW, Yao KM, Shiu SY. Signaling mechanisms of melatonin in antiproliferation of hormone-refractory 22Rv1 human prostate cancer cells: implications for prostate cancer chemoprevention. J Pineal Res. 2007;42:191–202.

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23:27–47.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Som P, Atkins HL, Bandoypadhyay D, Fowler JS, MacGregor RR, Matsui K, Oster ZH, Sacker DF, Shiue CY, Turner H, et al. A fluorinated glucose analog, 2-fluoro-2-deoxy-D-glucose (F-18): nontoxic tracer for rapid tumor detection. J Nucl Med. 1980;21:670–5.

    CAS  PubMed  Google Scholar 

  130. 130.

    Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8:519–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Dakubo GD, Parr RL, Costello LC, Franklin RB, Thayer RE. Altered metabolism and mitochondrial genome in prostate cancer. J Clin Pathol. 2006;59:10–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Costello LC, Feng P, Milon B, Tan M, Franklin RB. Role of zinc in the pathogenesis and treatment of prostate cancer: critical issues to resolve. Prostate Cancer Prostatic Dis. 2004;7:111–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Costello LC, Franklin RB. The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots. Mol Cancer. 2006;5:17.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  134. 134.

    Zadra G, Photopoulos C, Loda M. The fat side of prostate cancer. Biochim Biophys Acta. 2013;1831:1518–32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Cooper JF, Farid I. The role of citric acid in the physiology of the prostate. 3. Lactate/citrate ratios in benign and malignant prostatic homogenates as an index of prostatic malignancy. J Urol. 1964;92:533–6.

    CAS  PubMed  Article  Google Scholar 

  136. 136.

    Costello LC, Franklin RB. The intermediary metabolism of the prostate: a key to understanding the pathogenesis and progression of prostate malignancy. Oncology. 2000;59:269–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. 137.

    Costello LC, Liu Y, Franklin RB, Kennedy MC. Zinc inhibition of mitochondrial aconitase and its importance in citrate metabolism of prostate epithelial cells. J Biol Chem. 1997;272:28875–81.

    CAS  PubMed  Article  Google Scholar 

  138. 138.

    Mondul AM, Moore SC, Weinstein SJ, Karoly ED, Sampson JN, Albanes D. Metabolomic analysis of prostate cancer risk in a prospective cohort: the alpha-tocolpherol, beta-carotene cancer prevention (ATBC) study. Int J Cancer. 2015;137:2124–32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Dueregger A, Schopf B, Eder T, Hofer J, Gnaiger E, Aufinger A, Kenner L, Perktold B, Ramoner R, Klocker H, Eder IE. Differential utilization of dietary fatty acids in benign and malignant cells of the prostate. PLoS ONE. 2015;10:e0135704.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  140. 140.

    Testa C, Pultrone C, Manners DN, Schiavina R, Lodi R. Metabolic imaging in prostate cancer: where we are. Front Oncol. 2016;6:225.

    PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Schoder H, Larson SM. Positron emission tomography for prostate, bladder, and renal cancer. Semin Nucl Med. 2004;34:274–92.

    PubMed  Article  Google Scholar 

  142. 142.

    Costa EJ, Shida CS, Biaggi MH, Ito AS, Lamy-Freund MT. How melatonin interacts with lipid bilayers: a study by fluorescence and ESR spectroscopies. FEBS Lett. 1997;416:103–6.

    CAS  PubMed  Article  Google Scholar 

  143. 143.

    Le Bars D, Thivolle P, Vitte PA, Bojkowski C, Chazot G, Arendt J, Frackowiak RS, Claustrat B. PET and plasma pharmacokinetic studies after bolus intravenous administration of [11C]melatonin in humans. Int J Rad Appl Instrum B. 1991;18:357–62.

    PubMed  Article  Google Scholar 

  144. 144.

    Hevia D, Sainz RM, Blanco D, Quiros I, Tan DX, Rodriguez C, Mayo JC. Melatonin uptake in prostate cancer cells: intracellular transport versus simple passive diffusion. J Pineal Res. 2008;45:247–57.

    CAS  PubMed  Article  Google Scholar 

  145. 145.

    Hevia D, Gonzalez-Menendez P, Quiros-Gonzalez I, Miar A, Rodriguez-Garcia A, Tan DX, Reiter RJ, Mayo JC, Sainz RM. Melatonin uptake through glucose transporters: a new target for melatonin inhibition of cancer. J Pineal Res. 2015;58:234–50.

    CAS  PubMed  Article  Google Scholar 

  146. 146.

    Chandler JD, Williams ED, Slavin JL, Best JD, Rogers S. Expression and localization of GLUT1 and GLUT12 in prostate carcinoma. Cancer. 2003;97:2035–42.

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Georgescu I, Gooding RJ, Doiron RC, Day A, Selvarajah S, Davidson C, Berman DM, Park PC. Molecular characterization of Gleason patterns 3 and 4 prostate cancer using reverse Warburg effect-associated genes. Cancer Metab. 2016;4:8.

    PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Reinicke K, Sotomayor P, Cisterna P, Delgado C, Nualart F, Godoy A. Cellular distribution of Glut-1 and Glut-5 in benign and malignant human prostate tissue. J Cell Biochem. 2012;113:553–62.

    CAS  PubMed  Article  Google Scholar 

  149. 149.

    Xiao H, Wang J, Yan W, Cui Y, Chen Z, Gao X, Wen X, Chen J. GLUT1 regulates cell glycolysis and proliferation in prostate cancer. Prostate. 2018;78:86–94.

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Mayo JC, Sainz RM, Gonzalez-Menendez P, Hevia D, Cernuda-Cernuda R. Melatonin transport into mitochondria. Cell Mol Life Sci. 2017;74:3927–40.

    CAS  PubMed  Article  Google Scholar 

  151. 151.

    Huo X, Wang C, Yu Z, Peng Y, Wang S, Feng S, Zhang S, Tian X, Sun C, Liu K, et al. Human transporters, PEPT1/2, facilitate melatonin transportation into mitochondria of cancer cells: an implication of the therapeutic potential. J Pineal Res. 2017;62:536.

    Article  CAS  Google Scholar 

  152. 152.

    Hevia D, Gonzalez-Menendez P, Fernandez-Fernandez M, Cueto S, Rodriguez-Gonzalez P, Garcia-Alonso JI, Mayo JC, Sainz RM. Melatonin decreases glucose metabolism in prostate cancer cells: a (13)C stable isotope-resolved metabolomic study. Int J Mol Sci. 2017;18:1620.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  153. 153.

    Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer. 2002;2:727–39.

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–57.

    CAS  PubMed  Article  Google Scholar 

  155. 155.

    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    CAS  Article  Google Scholar 

  156. 156.

    Jiang J, Chen Y, Zhu Y, Yao X, Qi J. Contrast-enhanced ultrasonography for the detection and characterization of prostate cancer: correlation with microvessel density and Gleason score. Clin Radiol. 2011;66:732–7.

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Mukherji D, Temraz S, Wehbe D, Shamseddine A. Angiogenesis and anti-angiogenic therapy in prostate cancer. Crit Rev Oncol Hematol. 2013;87:122–31.

    PubMed  Article  Google Scholar 

  158. 158.

    Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol. 1993;143:401–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Duque JL, Loughlin KR, Adam RM, Kantoff PW, Zurakowski D, Freeman MR. Plasma levels of vascular endothelial growth factor are increased in patients with metastatic prostate cancer. Urology. 1999;54:523–7.

    CAS  PubMed  Article  Google Scholar 

  160. 160.

    Green MM, Hiley CT, Shanks JH, Bottomley IC, West CM, Cowan RA, Stratford IJ. Expression of vascular endothelial growth factor (VEGF) in locally invasive prostate cancer is prognostic for radiotherapy outcome. Int J Radiat Oncol Biol Phys. 2007;67:84–90.

    CAS  PubMed  Article  Google Scholar 

  161. 161.

    Sordello S, Bertrand N, Plouet J. Vascular endothelial growth factor is up-regulated in vitro and in vivo by androgens. Biochem Biophys Res Commun. 1998;251:287–90.

    CAS  PubMed  Article  Google Scholar 

  162. 162.

    Kimbro KS, Simons JW. Hypoxia-inducible factor-1 in human breast and prostate cancer. Endocr Relat Cancer. 2006;13:739–49.

    CAS  PubMed  Article  Google Scholar 

  163. 163.

    Mabjeesh NJ, Willard MT, Frederickson CE, Zhong H, Simons JW. Androgens stimulate hypoxia-inducible factor 1 activation via autocrine loop of tyrosine kinase receptor/phosphatidylinositol 3’-kinase/protein kinase B in prostate cancer cells. Clin Cancer Res. 2003;9:2416–25.

    CAS  PubMed  Google Scholar 

  164. 164.

    Halin S, Hammarsten P, Wikstrom P, Bergh A. Androgen-insensitive prostate cancer cells transiently respond to castration treatment when growing in an androgen-dependent prostate environment. Prostate. 2007;67:370–7.

    PubMed  Article  Google Scholar 

  165. 165.

    Shabsigh A, Ghafar MA, de la Taille A, Burchardt M, Kaplan SA, Anastasiadis AG, Buttyan R. Biomarker analysis demonstrates a hypoxic environment in the castrated rat ventral prostate gland. J Cell Biochem. 2001;81:437–44.

    CAS  PubMed  Article  Google Scholar 

  166. 166.

    Mitani T, Harada N, Nakano Y, Inui H, Yamaji R. Coordinated action of hypoxia-inducible factor-1alpha and beta-catenin in androgen receptor signaling. J Biol Chem. 2012;287:33594–606.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. 167.

    Lissoni P, Rovelli F, Malugani F, Bucovec R, Conti A, Maestroni GJ. Anti-angiogenic activity of melatonin in advanced cancer patients. Neuro Endocrinol Lett. 2001;22:45–7.

    CAS  PubMed  Google Scholar 

  168. 168.

    Kim KJ, Choi JS, Kang I, Kim KW, Jeong CH, Jeong JW. Melatonin suppresses tumor progression by reducing angiogenesis stimulated by HIF-1 in a mouse tumor model. J Pineal Res. 2013;54:264–70.

    CAS  PubMed  Article  Google Scholar 

  169. 169.

    Leon J, Casado J, Jimenez Ruiz SM, Zurita MS, Gonzalez-Puga C, Rejon JD, Gila A, Munozde Rueda P, Pavon EJ, Reiter RJ, et al. Melatonin reduces endothelin-1 expression and secretion in colon cancer cells through the inactivation of FoxO-1 and NF-kappabeta. J Pineal Res. 2014;56:415–26.

    CAS  PubMed  Article  Google Scholar 

  170. 170.

    Park SY, Jang WJ, Yi EY, Jang JY, Jung Y, Jeong JW, Kim YJ. Melatonin suppresses tumor angiogenesis by inhibiting HIF-1alpha stabilization under hypoxia. J Pineal Res. 2010;48:178–84.

    CAS  PubMed  Article  Google Scholar 

  171. 171.

    Park JW, Hwang MS, Suh SI, Baek WK. Melatonin down-regulates HIF-1 alpha expression through inhibition of protein translation in prostate cancer cells. J Pineal Res. 2009;46:415–21.

    CAS  PubMed  Article  Google Scholar 

  172. 172.

    Cho SY, Lee HJ, Jeong SJ, Lee HJ, Kim HS, Chen CY, Lee EO, Kim SH. Sphingosine kinase 1 pathway is involved in melatonin-induced HIF-1alpha inactivation in hypoxic PC-3 prostate cancer cells. J Pineal Res. 2011;51:87–93.

    CAS  PubMed  Article  Google Scholar 

  173. 173.

    Ader I, Malavaud B, Cuvillier O. When the sphingosine kinase 1/sphingosine 1-phosphate pathway meets hypoxia signaling: new targets for cancer therapy. Cancer Res. 2009;69:3723–6.

    CAS  PubMed  Article  Google Scholar 

  174. 174.

    Cortez MA, Bueso-Ramos C, Ferdin J, Lopez-Berestein G, Sood AK, Calin GA. MicroRNAs in body fluids–the mix of hormones and biomarkers. Nat Rev Clin Oncol. 2011;8:467–77.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. 175.

    Romero-Cordoba SL, Salido-Guadarrama I, Rodriguez-Dorantes M, Hidalgo-Miranda A. miRNA biogenesis: biological impact in the development of cancer. Cancer Biol Ther. 2014;15:1444–55.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. 176.

    Sohn EJ, Won G, Lee J, Lee S, Kim SH. Upregulation of miRNA3195 and miRNA374b mediates the anti-angiogenic properties of melatonin in hypoxic PC-3 prostate cancer cells. J Cancer. 2015;6:19–28.

    PubMed  PubMed Central  Article  Google Scholar 

  177. 177.

    Zelivianski S, Verni M, Moore C, Kondrikov D, Taylor R, Lin MF. Multipathways for transdifferentiation of human prostate cancer cells into neuroendocrine-like phenotype. Biochim Biophys Acta. 2001;1539:28–43.

    CAS  PubMed  Article  Google Scholar 

  178. 178.

    Yuan TC, Veeramani S, Lin MF. Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells. Endocr Relat Cancer. 2007;14:531–47.

    CAS  PubMed  Article  Google Scholar 

  179. 179.

    Ismail AH, Landry F, Aprikian AG, Chevalier S. Androgen ablation promotes neuroendocrine cell differentiation in dog and human prostate. Prostate. 2002;51:117–25.

    Article  CAS  Google Scholar 

  180. 180.

    Ito T, Yamamoto S, Ohno Y, Namiki K, Aizawa T, Akiyama A, Tachibana M. Up-regulation of neuroendocrine differentiation in prostate cancer after androgen deprivation therapy, degree and androgen independence. Oncol Rep. 2001;8:1221–4.

    CAS  PubMed  Google Scholar 

  181. 181.

    Bang YJ, Pirnia F, Fang WG, Kang WK, Sartor O, Whitesell L, Ha MJ, Tsokos M, Sheahan MD, Nguyen P, et al. Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP. Proc Natl Acad Sci USA. 1994;91:5330–4.

    CAS  PubMed  Article  Google Scholar 

  182. 182.

    Burchardt T, Burchardt M, Chen MW, Cao Y, de la Taille A, Shabsigh A, Hayek O, Dorai T, Buttyan R. Transdifferentiation of prostate cancer cells to a neuroendocrine cell phenotype in vitro and in vivo. J Urol. 1999;162:1800–5.

    CAS  PubMed  Article  Google Scholar 

  183. 183.

    Adler HL, McCurdy MA, Kattan MW, Timme TL, Scardino PT, Thompson TC. Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. J Urol. 1999;161:182–7.

    CAS  PubMed  Article  Google Scholar 

  184. 184.

    Drachenberg DE, Elgamal AA, Rowbotham R, Peterson M, Murphy GP. Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate. 1999;41:127–33.

    CAS  PubMed  Article  Google Scholar 

  185. 185.

    Adam RM, Kim J, Lin J, Orsola A, Zhuang L, Rice DC, Freeman MR. Heparin-binding epidermal growth factor-like growth factor stimulates androgen-independent prostate tumor growth and antagonizes androgen receptor function. Endocrinology. 2002;143:4599–608.

    CAS  PubMed  Article  Google Scholar 

  186. 186.

    Gutierrez-Canas I, Juarranz MG, Collado B, Rodriguez-Henche N, Chiloeches A, Prieto JC, Carmena MJ. Vasoactive intestinal peptide induces neuroendocrine differentiation in the LNCaP prostate cancer cell line through PKA, ERK, and PI3K. Prostate. 2005;63:44–55.

    CAS  PubMed  Article  Google Scholar 

  187. 187.

    Gilad E, Laudon M, Matzkin H, Zisapel N. Evidence for a local action of melatonin on the rat prostate. J Urol. 1998;159:1069–73.

    CAS  PubMed  Article  Google Scholar 

  188. 188.

    Sainz RM, Mayo JC, Tan DX, Leon J, Manchester L, Reiter RJ. Melatonin reduces prostate cancer cell growth leading to neuroendocrine differentiation via a receptor and PKA independent mechanism. Prostate. 2005;63:29–43.

    CAS  PubMed  Article  Google Scholar 

  189. 189.

    Mayo JC, Hevia D, Quiros-Gonzalez I, Rodriguez-Garcia A, Gonzalez-Menendez P, Cepas V, Gonzalez-Pola I, Sainz RM. IGFBP3 and MAPK/ERK signaling mediates melatonin-induced antitumor activity in prostate cancer. J Pineal Res. 2017;62:945.

    Google Scholar 

  190. 190.

    Rodriguez-Garcia A, Mayo JC, Hevia D, Quiros-Gonzalez I, Navarro M, Sainz RM. Phenotypic changes caused by melatonin increased sensitivity of prostate cancer cells to cytokine-induced apoptosis. J Pineal Res. 2013;54:33–45.

    CAS  PubMed  Article  Google Scholar 

  191. 191.

    Wang Z, Zhao Y, An Z, Li W. Molecular links between angiogenesis and neuroendocrine phenotypes in prostate cancer progression. Front Oncol. 2019;9:1491.

    PubMed  Article  Google Scholar 

  192. 192.

    Grobholz R, Bohrer MH, Siegsmund M, Junemann KP, Bleyl U, Woenckhaus M. Correlation between neovascularisation and neuroendocrine differentiation in prostatic carcinoma. Pathol Res Pract. 2000;196:277–84.

    CAS  PubMed  Article  Google Scholar 

  193. 193.

    Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407:770–6.

    CAS  PubMed  Article  Google Scholar 

  194. 194.

    Norbury CJ, Hickson ID. Cellular responses to DNA damage. Annu Rev Pharmacol Toxicol. 2001;41:367–401.

    CAS  PubMed  Article  Google Scholar 

  195. 195.

    Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;267:1456–62.

    CAS  PubMed  Article  Google Scholar 

  196. 196.

    Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116:205–19.

    CAS  PubMed  Article  Google Scholar 

  197. 197.

    Kiedrowski M, Mroz A. The effects of selected drugs and dietary compounds on proliferation and apoptosis in colorectal carcinoma. Contemp Oncol (Pozn). 2014;18:222–6.

    Google Scholar 

  198. 198.

    Savill J, Fadok V. Corpse clearance defines the meaning of cell death. Nature. 2000;407:784–8.

    CAS  PubMed  Article  Google Scholar 

  199. 199.

    Hong Y, Won J, Lee Y, Lee S, Park K, Chang KT, Hong Y. Melatonin treatment induces interplay of apoptosis, autophagy, and senescence in human colorectal cancer cells. J Pineal Res. 2014;56:264–74.

    CAS  PubMed  Article  Google Scholar 

  200. 200.

    Joo SS, Yoo YM. Melatonin induces apoptotic death in LNCaP cells via p38 and JNK pathways: therapeutic implications for prostate cancer. J Pineal Res. 2009;47:8–14.

    CAS  PubMed  Article  Google Scholar 

  201. 201.

    Sainz RM, Reiter RJ, Tan DX, Roldan F, Natarajan M, Quiros I, Hevia D, Rodriguez C, Mayo JC. Critical role of glutathione in melatonin enhancement of tumor necrosis factor and ionizing radiation-induced apoptosis in prostate cancer cells in vitro. J Pineal Res. 2008;45:258–70.

    CAS  PubMed  Article  Google Scholar 

  202. 202.

    Flo A, Calpena AC, Halbaut L, Araya EI, Fernandez F, Clares B. Melatonin delivery: transdermal and transbuccal evaluation in different vehicles. Pharm Res. 2016;33:1615–27.

    CAS  PubMed  Article  Google Scholar 

  203. 203.

    Lissoni P, Barni S, Meregalli S, Fossati V, Cazzaniga M, Esposti D, Tancini G. Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone. Br J Cancer. 1995;71:854–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  204. 204.

    Bas E, Naziroglu M. Treatment with melatonin and selenium attenuates docetaxel-induced apoptosis and oxidative injury in kidney and testes of mice. Andrologia. 2019;51:e13320.

    PubMed  Article  CAS  Google Scholar 

  205. 205.

    Ma Z, Yang Y, Fan C, Han J, Wang D, Di S, Hu W, Liu D, Li X, Reiter RJ, Yan X. Melatonin as a potential anticarcinogen for non-small-cell lung cancer. Oncotarget. 2016;7:46768–84.

    PubMed  PubMed Central  Article  Google Scholar 

  206. 206.

    Wang J, Guo W, Chen W, Yu W, Tian Y, Fu L, Shi D, Tong B, Xiao X, Huang W, Deng W. Melatonin potentiates the antiproliferative and pro-apoptotic effects of ursolic acid in colon cancer cells by modulating multiple signaling pathways. J Pineal Res. 2013;54:406–16.

    CAS  PubMed  Article  Google Scholar 

  207. 207.

    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;54:1299–321.

    CAS  PubMed  Article  Google Scholar 

  208. 208.

    Tamarindo GH, Ribeiro DL, Gobbo MG, Guerra LHA, Rahal P, Taboga SR, Gadelha FR, Goes RM. Melatonin and docosahexaenoic acid decrease proliferation of PNT1A prostate benign cells via modulation of mitochondrial bioenergetics and ROS production. Oxid Med Cell Longev. 2019;2019:5080798.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  209. 209.

    Terraneo L, Bianciardi P, Virgili E, Finati E, Samaja M, Paroni R. Transdermal administration of melatonin coupled to cryopass laser treatment as noninvasive therapy for prostate cancer. Drug Deliv. 2017;24:979–85.

    CAS  PubMed  Article  Google Scholar 

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We gratefully acknowledge excellent technical assistance provided by Ms. Yuan Zhu and Ms. Yayun Fang from Zhongnan Hospital of Wuhan University.


This study was supported by the Health commission of Hubei Province scientific research project (WJ2019H080) and Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2020-PT320-004).

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DS and LJ planned the organization of the review and wrote the first draft. DS, LJ, FZ, MY, HM and YZ helped with data collection and complete the manuscript. DS, LJ, FZ, TL, YX, XW and KQ helped with the final correction. All authors have approved the final manuscript.

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Correspondence to Yu Xiao or Xinghuan Wang or Kaiyu Qian.

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Shen, D., Ju, L., Zhou, F. et al. The inhibitory effect of melatonin on human prostate cancer. Cell Commun Signal 19, 34 (2021).

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  • Prostate cancer
  • Melatonin
  • AR
  • ADT
  • P27Kip1