Melatonin
Significantly suppressed the expression of angiogenesis-related proteins HIF-1α, HIF-2α and VEGF across cancer and non-cancer cells (Kidney Cancer included).
Reduced the risk of death by 37% across cancer types in RCTs (Kidney Cancer included), while improving the treatment response rates.
Has other systematic effects on human body such as rejuvenating the thymus gland.
An anti-aging intervention, as it improves lifespan across different animal models including mice.
Typical dose in cancer studies is 20mg/day.
Melatonin as a potential inhibitor of kidney cancer: A survey of the molecular processes.
Sep 14, 2020
Melatonin plays a role in cancer therapy due to its anti-tumor effects as well as by enhancing the efficacy of other drugs as an adjuvant. In this review, we discuss different roles of melatonin in the treatment of kidney cancer. The studies concerned with the applications of melatonin as an adjuvant in the immunotherapy of patients with kidney cancer are summarized. Also, we highlight the apoptotic and anti-angiogenic effects of melatonin on renal cancer cells which are mediated by different molecules (e.g., HIF-1 and VEGF, ADAMTS1, and MMP-9) and signaling pathways (e.g., P56, P52, and JNK). Furthermore, we take a look into available data on melatonin’s ability to reduce the toxicities caused by kidney carcinogens, including ochratoxin A, potassium bromate, and Fe-NTA.
Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis, 2005
We included 10 RCTs published between 1992 and 2003 and included 643 patients. All trials included solid tumor cancers. All trials were conducted at the same hospital network, and were unblinded. Melatonin reduced the risk of death at 1 yr (relative risk: 0.66, 95% confidence interval: 0.59–0.73, I2 = 0%, heterogeneity P ≤ 0.56). Effects were consistent across melatonin dose, and type of cancer. No severe adverse events were reported. The substantial reduction in risk of death, low adverse events reported and low costs related to this intervention suggest great potential for melatonin in treating cancer.
Melatonin significantly suppressed the expression of angiogenesis-related proteins HIF-1α, HIF-2α and VEGF at mRNA level of PC-3 (prostate cancer) cells under hypoxia, and upregulation of miRNA3195 and miRNA374b could mediate this anti-angiogenic property of melatonin [93].
Melatonin suppresses tumor angiogenesis by inhibiting HIF-1alpha stabilization under hypoxia.
Angiogenesis is an important mediator of tumor progression. As tumors expand, diffusion distances from the existing vascular supply increases, resulting in hypoxia in the cancer cells. Sustained expansion of a tumor mass requires new blood vessel formation to provide rapidly proliferating tumor cells with an adequate supply of oxygen and nutrients. The key regulator of hypoxia-induced angiogenesis is the transcription factor known as hypoxia-inducible factor (HIF)-1. HIF-1alpha is stabilized by hypoxia-induced reactive oxygen species (ROS) and enhances the expression of several types of hypoxic genes, including that of the angiogenic activator known as vascular endothelial cell growth factor (VEGF). In this study, we found that melatonin, a small lipophilic molecule secreted primarily by the pineal gland, destabilizes hypoxia-induced HIF-1alpha protein levels in the HCT116 human colon cancer cell line. This destabilization of HIF-1alpha resulted from the antioxidant activity of melatonin against ROS induced by hypoxia. Moreover, under hypoxia, melatonin suppressed HIF-1 transcriptional activity, leading to a decrease in VEGF expression.
Melatonin as adjuvant cancer care with and without chemotherapy: A systematic review and meta-analysis of randomized trials, 2012
The authors included data from 21 clinical trials, all of which dealt with solid tumors. The pooled relative risk (RR) for 1-year mortality was 0.63 (95% confidence interval [CI] = 0.53-0.74; P < .001). Improved effect was found for complete response, partial response, and stable disease with RRs of 2.33 (95% CI = 1.29-4.20), 1.90 (1.43-2.51), and 1.51 (1.08-2.12), respectively. In trials combining MLT with chemotherapy, adjuvant MLT decreased 1-year mortality (RR = 0.60; 95% CI = 0.54-0.67) and improved outcomes of complete response, partial response, and stable disease; pooled RRs were 2.53 (1.36-4.71), 1.70 (1.37-2.12), and 1.15 (1.00-1.33), respectively. In these studies, MLT also significantly reduced asthenia, leucopenia, nausea and vomiting, hypotension, and thrombocytopenia.
Abrogation of the Negative Influence of Opioids on IL–2 Immunotherapy of Renal Cell Cancer by Melatonin, 2000
IL–2 immunotherapy has been proven to be effective in the treatment of metastatic renal cell cancer (RCC). However, several drugs commonly used in the palliative therapy of cancer may potentially influence IL–2 efficacy, since the anticancer immunity has appeared to depend on complex interactions between immune system and psychoneuroimmunomodulation. In particular, experimental studies and preliminary clinical investigations have shown that the opioid substances, namely morphine, may suppress the anticancer immunity and the efficacy of IL–2 itself. In contrast, other neuroactive substances, in particular the pineal hormone melatonin (MLT), have been proven to stimulate the immune response, including the anticancer immunity, and to abrogate opioid–induced immunosuppression. On this basis, a study was planned to evaluate the effect of a concomitant MLT administration on the efficacy of IL–2 immunotherapy in advanced cancer patients chronically treated with morphine for cancer–related pain. The study was carried out in 30 metastatic RCC patients under chronic therapy with morphine at oral doses ranging from 60 to 120 mg/day. Patients were randomized to receive morphine alone or morphine plus MLT (20 mg/day orally in the evening). The immunotherapeutic cycle consisted of IL–2 subcutaneous administration at a dose of 6 million IU/day for 6 days/week for 4 consecutive weeks. In nonprogressing patients, a second cycle was planned after a 21–day rest period. The percent of partial responses achieved in patients treated with morphine alone was significantly lower than that observed in patients concomitantly treated with MLT (1/16 vs. 4/14, p<0.05). Moreover, the 3–year percent of survival was significantly higher in patients concomitantly treated with MLT (p<0.01). In contrast, no diminished analgesic efficacy of morphine occurred in patients concomitantly treated with MLT. This preliminary study seems to suggest that the negative influence of morphine therapy for cancer–related pain on the clinical efficacy of IL–2 cancer immunotherapy may be abrogated by the concomitant administration of the immunomodulating pineal neurohormone MLT.
Melatonin for the prevention and treatment of cancer (link)
A recent study systematically investigated the anti-metastatic effect of melatonin on renal cell carcinoma (RCC) [135]. Melatonin inhibited MMP-9 transactivation and tumor metastasis though inhibiting Akt-MAPKs pathway and NF-κB DNA-binding activity. Moreover, clinical sample analysis found a higher survival rate in MTNR1Ahigh/MMP-9low patients than in MTNR1Alow/MMP-9high patients [135]. Melatonin also induced apoptosis by upregulating the expression of Bim in renal cancer Caki cells, at both transcriptional level and post-translational level [136]. Furthermore, co-treatment of melatonin (1 mM) and thapsigargin (50 nM) induced more apoptosis in human renal cancer cells than treatment with thapsigargin alone, which was through ROS-mediated upregulation of CCAAT-enhancer-binding protein homologous protein [137]. Co-treatment of melatonin and kahweol induced apoptosis, stimulated DEVDase activity (could reflect caspase-3 activity), and DNA fragmentation of Caki renal cancer cells. The mechanism underlying was elucidated as inducing upregulation of p53-upregulated modulator of apoptosis [138].
Collectively, inducing apoptosis and inhibiting metastasis are the main effects of melatonin on renal cancer cells. Moreover, concomitant melatonin ministration with other therapies might be an effective clinical choice for patients with renal cancer.
Melatonin as antioxidant, geroprotector and anticarcinogen
In female CBA, SHR, SAM and transgenic HER-2/neu mice long-term administration of melatonin was followed by an increase in the mean life span. In rats, melatonin treatment increased survival of male and female rats. In D. melanogaster (fruit fly), increase in the longevity of fruit flies has been observed when melatonin was added to food throughout the life span.
Optimizing Oxidation in the Care of Chronically Ill Patients
Melatonin - Better than expected (link)
(Great talk on cancer and longevity benefits)
Melatonin Stops Estrogen Conversion Just Like Strong Drugs
Benefits of Melatonin (increase your longevity?)
Daily Nighttime Melatonin Reduces Blood Pressure in Male Patients With Essential Hypertension (2004)
Patients with essential hypertension have disturbed autonomic cardiovascular regulation and circadian pacemaker function. Recently, the biological clock was shown to be involved in autonomic cardiovascular regulation. Our objective was to determine whether enhancement of the functioning of the biological clock by repeated nighttime melatonin intake might reduce ambulatory blood pressure in patients with essential hypertension. We conducted a randomized, double-blind, placebo-controlled, crossover trial in 16 men with untreated essential hypertension to investigate the influence of acute (single) and repeated (daily for 3 weeks) oral melatonin (2.5 mg) intake 1 hour before sleep on 24-hour ambulatory blood pressure and actigraphic estimates of sleep quality. Repeated melatonin intake reduced systolic and diastolic blood pressure during sleep by 6 and 4 mm Hg, respectively. The treatment did not affect heart rate. The day–night amplitudes of the rhythms in systolic and diastolic blood pressures were increased by 15% and 25%, respectively. A single dose of melatonin had no effect on blood pressure. Repeated (but not acute) melatonin also improved sleep. Improvements in blood pressure and sleep were statistically unrelated. In patients with essential hypertension, repeated bedtime melatonin intake significantly reduced nocturnal blood pressure. Future studies in larger patient group should be performed to define the characteristics of the patients who would benefit most from melatonin intake. The present study suggests that support of circadian pacemaker function may provide a new strategy in the treatment of essential hypertension.
Melatonin increases overall survival of prostate cancer patients with poor prognosis after combined hormone radiation treatment
October 13, 2020
Background: The antitumor and immunomodulating activities of melatonin are widely known. These activities are based upon the multifactorial mechanism of action on various links of carcinogenesis. In the present paper, the long-term results of the clinical use of melatonin in the combined treatment of patients with prostate cancer of various risk groups were evaluated.
Materials and Methods: A retrospective study included 955 patients of various stages of prostate cancer (PCa) who received combined hormone radiation treatment from 2000 to 2019. Comprehensive statistical methods were used to analyze the overall survival rate of PCa patients treated with melatonin in various prognosis groups.
Results: The overall survival rate of PCa patients with favorable and intermediate prognoses treated or not treated with melatonin was not statistically significantly different. In the poor prognosis group, the median overall survival in patients taking the drug was 153.5 months versus 64.0 months in patients not using it (p < 0.0001). The 5-year overall survival rates in the research and control groups were 66.8 ± 1.9 and 53.7 ± 2.6 (p < 0.0001) respectively. In a multivariate analysis, melatonin administration proved to be an independent prognostic factor and reduced the risk of death of PCa patients by more than twice (p < 0.0001).
Conclusions: The multicomponent antitumor effect of melatonin is fully realized and clearly demonstrated in treatment of PCa patients with poor prognosis with a set of unfavorable factors of the tumor progression.
Melatonin Rejuvenates the Thymus Gland (link)
The thymus gland is key to immunity and longevity. As we age it becomes involuted and eventually stops functioning. (The effects become more problematic later in life.)
This study confirms that giving melatonin in the drinking water of mice reverses the involution.
Melatonin is easily available as a supplement in many countries. We can also raise our levels naturally by getting early morning sun exposure.
Involution can also be reversed by increasing human growth hormone in ways we've talked about in this group.
Exogenous melatonin was administered through the drinking water (15 microg/ml) of 22-month-old female C57BL mice for 60 consecutive days. Our results show that melatonin distinctly reversed the age-related thymic involution as revealed by the notable increase of thymus weight, total number of thymocytes and percentage of thymocytes at G2+S phases. More strikingly, spleen weight, total number of splenocytes and some peripheral immune capacity such as mitogen responsiveness and NK cell activity were also significantly recovered by 60 days of melatonin application in aged mice. Our findings demonstrate that even when the melatonin supplementation begins late in life, the age-related thymic involution and peripheral immune dysfunctions can be restored at least partially in old mice.
Effects of Exogenous Melatonin—A Review, 2003
The results of studies on the effect of pineal indole hormone melatonin on the life span of mice, rats, fruit flies, and worms are critically reviewed. In mice, long-term administration of melatonin was followed by an increase in their life span in 12 experiments and had no effect in 8 of 20 different experiments. In D. melanogaster, the supplementation of melatonin to the nutrient medium during developmental stages gave contradictory results, but when melatonin was added to food throughout the life span, an increase in the longevity of fruit flies has been observed. Melatonin decreased the survival of C. elegans but increased the clonal life span of planaria Paramecium tertaurelia.
[Recommended dose 20mg/day or higher.]
Comments