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].
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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 G i /cGMP/Ca2+/PKC pathway. Melatonin stimulated G i 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 G q 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 G q protein presumably stimulated PLC or (PLD) to promote AR nuclear exclusion, and the process was inhibited by RGS4 Full size image
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 Full size image
“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.
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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, Gα s and Gα q , were continuously activated. Then Gα q directly activated PKC, while Gα s 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 Full size image
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].
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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.
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