New review paper from Spain below.
I have been using melatonin for PCa for 15 years. Initially at 40 mg before bed; ultimately at 50 mg as per change in LEF recommendation. But not before I reviewed the literature.
This is the PCa section:
"3. Melatonin and Hormone-Dependent Prostate Cancer
Prostate cancer (PC) is one of the leading causes of death by cancer among males in the developed world. As prostate physiology is under the control of androgens (testosterone and dihydrotestosterone) and their metabolites, androgen deprivation therapy (by inhibition of hormone biosynthesis or androgen receptor deprivation) has been extensively used in PC. However, most patients will develop hormone-refractory cancer [68]. As well as in the case of the mammary gland, the role of melatonin in the prostate has been established a long time ago. In vivo, melatonin (at a pharmacological dose of 150 mg/100 g of body weight, administered for 4 weeks) induced a significant decrease in the ventral prostate weight in castrated and castrated-testosterone-treated rats [69]. Conversely, pinealectomy was effective in stimulating androstenedione and testosterone production indicating an inhibitory action of the pineal gland on testicular steroidogenesis in rats [70]. Shortly after these findings, the involvement of melatonin in prostate cancer was unrevealed. In humans (patients with nonmetastasizing carcinoma), the pineal hormone did not show significant circadian rhythms indicating that the modulation of melatonin plasma levels might be related to prostate cancer genesis and growth [71]. Because of the antigonadotropic effect of melatonin, the hypothesis that the pineal hormone could inhibit prostate cancer was tested in vivo in rat prostatic adenocarcinoma. The main conclusion was that melatonin (50 μg/rat, daily injected one hour before darkness) suppressed the growth of prostate tumors [72]. Back to humans, when the circadian rhythms of melatonin and 6-sulfatoxymelatonin were analyzed in the serum of elder patients with primary prostate cancer, a reduced pineal activity was found [73]. Also in humans, a clinical combination of melatonin and the LHRH analogue triptorelin was tested in metastatic prostate cancer patients with promising results. The concomitant administration of melatonin (a therapeutic dose, orally administered at 20 mg/day, in the evening every day until progression, starting 7 days prior to triptorelin) may overcome the resistance to LHRH analogues and palliate the adverse side effects [74]. According to these results, a physiological dose of melatonin (1 nM) attenuated the growth of the human androgen-sensitive prostatic tumor cell line LNCaP in vitro [75]. The expression of the membrane Mel1a melatonin receptor was demonstrated in this cell line, and an accumulation of the cells in G0/G1 and a decrease in S phase were obtained by treatment with melatonin at nanomolar concentrations [76]. Interestingly, the direct oncostatic activity of melatonin (1 nM) was also demonstrated in vitro in human androgen-independent DU 145 prostate cancer cells. As occurred in breast cancer, the indoleamine caused cell-cycle withdrawal by accumulation of cells in G0/G1 and inhibition of cell proliferation [77]. Back to the androgen-responsive prostatic LNCaP cells, a melatonin-mediated nuclear exclusion of the androgen receptor (AR) was demonstrated, indicating that melatonin (used at concentrations ranging from 1 nM to 100 nM) might regulate AR activity [78]. At 100 nM, melatonin induced a rise in intracellular cGMP, leading to an increase in calcium levels and PKC activation [79]. In vivo experiments in rodents showed that epidermal growth factor (EGF) stimulated LNCaP tumor growth in nude mice and induced an increase in the levels of Cyclin D1, whereas melatonin (at a pharmacological dose of 4 mg/g of body weight, administered intraperitoneally 1 h before lighting was switched off) counteracted this effect [80]. An in vitro study evaluating the effect of melatonin in both androgen-dependent (LNCaP) and androgen-independent (PC3) cells demonstrated that treatment with the indoleamine (10 nM to 1 mM) dramatically reduced the number of both types of cells and, in addition, induced cellular differentiation. The effect of melatonin was not mediated by PKA although a transitory rise in cAMP levels was observed [81]. In androgen-dependent prostate cancer cells, it has been demonstrated that pharmacological doses of melatonin (ranging from 50 nM to 1 mM) increased p21 levels, decreased NF-κB activation, and Bcl-2 and survivin were downregulated [82]. The inhibition of NF-κB signaling via melatonin-dependent activation (melatonin dose: 10 nM) of PKA and PKC resulted in transcriptional upregulation of p27 (Kip1), a MT1-dependent antiproliferative signaling mechanism [83]. In LNCaP cells, the pineal hormone (at different concentrations from 0–3 mM) induced both early and late apoptosis, both dependent of activation of c-JUN kinase (JNK) and p38 kinase, strongly suggesting that these kinases directly participate in apoptosis triggered by melatonin [84]. In androgen-dependent but also in androgen-independent prostate cancer cell lines, melatonin (1 mM) seemed to exert an antiangiogenic effect since it reduced hypoxia-inducible factor (HIF-1) protein levels and the release of the vascular endothelial growth factor, which correlated with dephosphorylation of p70S6 kinase and its target, ribosomal protein RPS6 [85]. In prostate cancer cell lines (in vitro) and transgenic adenocarcinoma or mouse prostate (TRAMP) mice (in vivo), melatonin (dose: 10–20 mg/l in drinking water, for 18 weeks) inhibited tumorigenesis by decreasing the serum levels of IGF-1, IGFBP3, and proliferation markers such as PCNA and Ki-67. Sirt1, a NAD(+)-dependent histone deacetylase overexpressed in prostate cancer, was also inhibited by melatonin in correlation to a significant antiproliferative effect [86]. In vitro, in both androgen-sensitive LNCaP and insensitive PC-3 cell lines, the pineal hormone (1 mM) limited glycolysis, the tricarboxylic acid cycle, and the pentose phosphate pathways, indicating that melatonin slows down glucose metabolism in both prostate cancer cell lines [87]. Yet more molecular mechanisms have been recently characterized in vitro (prostate cancer cell lines) and in vivo (TRAMP mice models). KLK2, KLK3 (kallikreins), and IGF1R were downregulated, whereas IGFBP3 was upregulated by melatonin (pharmacological doses: 10–20 mg/l in drinking water, for 18 weeks), demonstrating the role of the IGF signaling pathways in the oncostatic effect of the pineal hormone [88]. Additionally, an increase in phosphorylation of Akt in melatonin-treated (dose: 18 i.p. injections at 1 mg/kg of body weight, treatment lasting for 41 days) nude mice in which LNCaP cells were xenografted has been demonstrated in vivo [89]. Recent evidence suggests that microRNAs (miRNAs) are good candidates to be considered as targets in cancer treatments. In androgen insensitive PC-3 lines subjected to hypoxia, melatonin (1 mM) upregulated miRNA3195 and miRNA374b. Overexpression of miRNA3195 and miRNA374b decreased the levels of the proangiogenic proteins VEGF, HIF-1, and HIF-2, thus explaining, at least in part, the antiangiogenic properties of melatonin in prostate cancer [90]. It is widely accepted that desynchronization of the clock circuitry after alterations in the circadian rhythms is implicated in cancer. Indeed, melatonin (100 μM to 2 mM) increased the levels of Per2 and Clock, whereas reduced Bmal1 in prostate cancer cells [91]. Combined with chemotherapeutic agents (etoposide, doxorubicin, or docetaxel), melatonin (1 mM) enhanced the sensitivity of cancer cells to cytokine-induced apoptosis in vitro [92].
"As in breast cancer, some attention has been drowned into the hypothesis that light-at-night (LAN) exposure can inhibit nocturnal melatonin, and consequently, prostate cancer risk would be elevated. The countries with higher levels of nocturnal light yielded a higher risk of prostate cancer [93]. Men who never worked at night in night-shift turns have a lower risk of prostate cancer in comparison with night-shift workers [94]. Men who reported sleep problems had lower morning levels of urinary 6-sulfatoxymelatonin in association with an increased prostate cancer risk [95]. Aggregate genetic variation in melatonin and circadian rhythms were also significantly associated with the risk of prostate cancer, but no significant association could be established for lung and ovarian cancer, supporting a potential role of melatonin pathways and circadian rhythms in prostate carcinogenesis [96]."
-Patrick
Full Text: hindawi.com/journals/ije/20...
Abstract: ncbi.nlm.nih.gov/pubmed/303...
Int J Endocrinol. 2018 Oct 2;2018:3271948. doi: 10.1155/2018/3271948. eCollection 2018.
Melatonin: An Anti-Tumor Agent in Hormone-Dependent Cancers.
Menéndez-Menéndez J1, Martínez-Campa C1.
Author information
1
Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain.
Abstract
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized and secreted by the pineal gland mainly during the night, since light exposure suppresses its production. Initially, an implication of this indoleamine in malignant disease was described in endocrine-responsive breast cancer. Data from several clinical trials and multiple experimental studies performed both in vivo and in vitro have documented that the pineal hormone inhibits endocrine-dependent mammary tumors by interfering with the estrogen signaling-mediated transcription, therefore behaving as a selective estrogen receptor modulator (SERM). Additionally, melatonin regulates the production of estradiol through the control of the enzymes involved in its synthesis, acting as a selective estrogen enzyme modulator (SEEM). Many more mechanisms have been proposed during the past few years, including signaling triggered after activation of the membrane melatonin receptors MT-1 and MT-2, or else intracellular actions targeting molecules such as calmodulin, or binding intranuclear receptors. Similar results have been obtained in prostate (regulation of enzymes involved in androgen synthesis and modulation of androgen receptor levels and activity) and ovary cancer. Thus, tumor metabolism, gene expression, or epigenetic modifications are modulated, cell growth is impaired and angiogenesis and metastasis are inhibited. In the last decade, many more reports have demonstrated that melatonin is a promising adjuvant molecule with many potential beneficial consequences when included in chemotherapy or radiotherapy protocols designed to treat endocrine-responsive tumors. Therefore, in this state-of-the-art review, we aim to compile the knowledge about the oncostatic actions of the indoleamine in hormone-dependent tumors, and the latest findings concerning melatonin actions when administered in combination with radio- or chemotherapy in breast, prostate, and ovary cancers. As melatonin has no toxicity, it may be well deserve to be considered as an endogenously generated agent helpful in cancer prevention and treatment.
PMID: 30386380 PMCID: PMC6189685 DOI: 10.1155/2018/3271948
