Effects Of Light Exposure At Night On Melatonin Secretion And Breast Cancer
Epidemiological studies indicate a higher risk for certain types of cancer in night shift workers. The International Agency for Research on Cancer recommended night shift work probably carcinogenic to humans . LAN has an influencing effect on breast cancer. The incidence of breast cancer shows 73% higher in LAN exposed individuals compared to the unexposed group . This finding is supported by the relationship between urinary melatonin excretion and the occurrence of breast cancer. An earlier study had indicated the low levels of urinary melatonin in human breast cancer patients . Devore et al. had indicated the relationship between urinary melatonin and the risk of breast cancer in postmenopausal women. They had included 1,354 postmenopausal women and measured 6-sulfatoxymelatonin from the first-morning spot urine. They reported that excretion of urinary melatonin had been associated with a lower risk of breast cancer in postmenopausal women. Elevated serum estradiol and low levels of urinary 6-sulfatoxymelatonin had been observed in postmenopausal women working at night that might be the pre-indicator of risk of breast cancer. However, this effect was not modified by the expression of the MT1 receptor in tumor cells .
Melatonin Supplementation To Improve Quality Of Life For Elderly Cancer Patients
Angeline Ginzac
Université Clermont Auvergne, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, F-63000 Clermont-Ferrand, France
Délégation Recherche Clinique & Innovation, Centre Jean Perrin, F-63011 Clermont-Ferrand, France
Emilie THIVAT
Université Clermont Auvergne, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, F-63000 Clermont-Ferrand, France
Délégation Recherche Clinique & Innovation, Centre Jean Perrin, F-63011 Clermont-Ferrand, France
Xavier Durando
Université Clermont Auvergne, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, F-63000 Clermont-Ferrand, France
Délégation Recherche Clinique & Innovation, Centre Jean Perrin, F-63011 Clermont-Ferrand, France
DOI: 10.15761/ICM.1000148
Melatonin As An Adjuvant To Radiotherapy
Emerging literature in the last few years has demonstrated that melatonin used alongside radiotherapy is able to augment the impact of ionizing radiation on tumors and can also prevent the latters toxic effects on non-cancerous cells. In vivo and in vitro scenarios have been deployed to examine melatonins radio-sensitizing properties a range of modes of action have been postulated for its activity in this regard .
Although multiple in vivo and in vitro studies have been performed in order to evaluate this phenomenon, the use of melatonin to enhance the effect of radiotherapy in human subjects has been poorly studied. Lissoni et al. were one of the first institutions to try to study melatonins influence on ionizing radiation they looked at this combination of treatment, using 60 Gy of radiation, in 30 patients presenting with glioblastomas. Their initial publication indicated that radiotherapy in combination with melatonin in this clinical cohort may improve life quality and increase the one-year survival statistics .
This positive outcome was not experienced in a randomized phase II clinical trial evaluating patients with cerebral metastases who were administered 30 Gy radiotherapy in 10 fractions in the afternoon, and were randomized to 20 mg melatonin which was prescribed for morning or evening administration. No clinical value with respect to either survival or neurological tumor progression was discerned .
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Medical Studies On Melatonin Cancer
There have been studies on melatonin as an effective anti-cancer hormone for several decades. It has been demonstrated to alleviate the symptoms of the early-stage, progression and metastasis phases and have a positive impact on the course of the disease. The anti-oxidative and immunoregulatory properties of melatonin and its effect on tumour-specific cell division are responsible for this.
Expression Of Other Nrs In Human Breast Cancer Cells By Melatonin
The decrease of ER- expression also regulates the transcriptional activity of other steroid hormones/NR super-family receptors. It is evident that melatonin can repress the ligand-induced expression of the glucocorticoid receptor and ROR- in breast cancer cells . Alternatively, melatonin can enhance the expression of other NRs, including retinoic acid X receptor alpha and the retinoic acid receptor alpha .
Dauchy et al. reported that melatonin administration during dLEN-mediated circadian disruption induced the expression and phosphorylation of many kinases that regulate the phosphorylation of NRs and other transcriptional factors . This event clearly expresses the importance of melatonin in the regulation of gene expression in human breast cancer cells. Furthermore, administration of melatonin along with all-trans-retinoic acid in MCF-7 cells induced the rate of apoptosis, which is mediated by increased expression of pro-apoptotic protein Bax and downregulation of TGF-1 and Bcl-2 expression . In addition, the combination of 9-cis retinoic acid and melatonin can inhibit the progression of N-nitroso-N-methyl urea -induced breast tumors in rats . In the presence of vitamin D, melatonin can promote vitamin D receptor transcriptional activity and drive the MCF-7 breast tumor cells towards apoptosis .
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Iii Results From Scientific Literature
Melatonin may have therapeutic value in patients with estrogen receptor -positive breast cancer. The growth of many mammary tumors depends, in part, on the presence of sex hormones known as estrogens . Synthesis of estrogens in the body is mediated by an enzyme called aromatase, which belongs to the cytochrome P450 family . Melatonin appears to reduce aromatase activity by downregulating upstream cyclooxygenase 2 signaling pathways, including ERK1/2, JNK, p38 MAPK, and NF-NF-kB . This change leads to falling concentrations of the tumor promoter prostaglandin E2 and cyclic adenosine monophosphate , which is a secondary messenger molecule key for signal transduction . In this context, reduced cAMP culminates in decreased activation of specific DNA sequences corresponding to aromatase production. Thus, by blocking aromatase production, melatonin impedes estrogen synthesis and the associated risk of breast cancer .
Inclusion And Exclusion Criteria Inclusion Criteria
1) The study was designed as a randomized controlled trial. 2) The study subjects were any type of cancer patients who were diagnosed by histological section, regardless of age, gender, and tumor stage. 3) The intervention group included MLT combined with other treatments . The control group received only other treatments . 4) Outcome indexes include at least one of the following three indicators: disease remission rate, overall survival rate, and incidence rate of adverse reactions. There are four outcomes after the use of antitumor drugs: complete remission , partial remission , stable disease , and disease progression . According to the WHO criteria, in CR, all tumor damages completely disappeared at least 1 month, in PR, the sum of the two longest diameters of tumor reduced by more than 50% for at least 1 month, SD, the sum of the two longest diameters of tumor reduced by more than 25%, or no tumor lesion, and in PD, the tumor damage increased by more than 25% or the appearance of new lesions. CR rate with PR rate equals disease remission rate.
Exclusion criteria
Animal studies, secondary literature studies, pharmacokinetic studies, nonrandomized controlled trials, and interventions such as non-MLT were excluded.
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Role And Therapeutic Potential Of Mlt On Prostate Cancer Cells
Prostate cancer ranks as the second-most frequent cancer and the fifth leading cause of cancer death in men.2,87 One of the crucial factors for prostate cancer is obesity.88 However, the rate of death has been decreasing owing to early diagnosis and treatment. A case-cohort study reported that men with low first-morning urinary levels of 6-sulphatoxymelatonin had a high risk of prostate cancer.89 Conversely, patients with high MLT-sulfate levels or a high MLT-sulfate/cortisol ratio were less likely to have prostate cancer.90 Pharmacological concentrations of MLT can inhibit the growth of androgen-dependent and -independent prostate cancer.91
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Figure 5 MLT targets mitochondria mediated apoptosis in prostate cancer cells. |
As A Single Anticancer Drug Or Adjuvant Anticancer Drug
Current evidence suggests melatonin to be used as an adjuvant or protective therapy. As an adjuvant therapy, it can increase the treatment efficacy as a protective therapy, it can ameliorate adverse side effects of chemo- and radiotherapy during cancer treatment .
Although melatonin has high efficacy and low toxicity in cancer treatment, very few companies want to develop this hormone, per se, as it is a natural and nonpatentable molecule. Moreover, despite numerous studies that have demonstrated the anticancer effects of melatonin, some studies also showed that the use of melatonin alone exerted less or even no effect on reducing cancer markers . Some epidemiological studies connecting the bodys circadian melatonin levels to cancer incidence concluded either significant or no associations . Melatonin exerted anti-proliferative and anti-migrating effects on a melanoma cell line, but similar effects could not be demonstrated in vivo . These inconsistent results also occurred in patients undergoing chemotherapy. A prospective cohort study investigating breast cancer patients undergoing chemotherapy showed that the repeated administration of chemotherapy dampened nocturnal melatonin production, which caused sleep disturbance and sleepwake activity rhythm disruption, suggesting that the supplementation of melatonin may improve the quality of life . However, this potential benefit of melatonin was not demonstrated in melanoma patients receiving dacarbazine .
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The Measurement Of Melatonin
Numerous beneficial roles of melatonin in modulating circadian rhythms and related disease have been reported. Hence, melatonin levels under various clinical and physiological conditions are important index values. However, how to precisely measure the melatonin concentration remains a huge challenge.
The fundamental problem is which sample should be collected: plasma, saliva, or urine. Endocrinology studies normally take blood samples to test for hormone levels and to assess the function of relevant glands. Since melatonin is secreted directly into the bloodstream, the measurement of melatonin in blood plasma is the most direct way. Melatonin levels in plasma are expected to be less than 5 pg/mL during the daytime . Therefore, the melatonin assay kits should have high sensitivity. Moreover, melatonin could also be found in saliva at night. Studies subsequently proved the correlation between plasma and saliva melatonin levels , despite that the use of salivary melatonin to speculate on serum concentration was once thought to be non-convincing . Furthermore, testing the 6-sulphatoxymelatonin level in urine is an accurate method to reflect the pineal melatonin . However, the commercial kits for urinary 6-sulphatoxymelatonin measurement could seldom achieve the standards set by mass spectrometry assays.
Effects Of Melatonin In Cancer
In healthy humans, the level of melatonin present in their body stays between a constant range depending on the time of day. However, in cancer patients, this range has been shown to drop down, which is why melatonin supplements can prove to be extremely useful when paired with the correct chemo/radiotherapy and the right cancer type.
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How Much Melatonin Should You Take
Melatonin should be considered as part of a comprehensive anti-cancer lifestyle and supplementation program, particularly in prostate cancer patients who also suffer from a sleep disorder like insomnia. Adequate dosing of 3mg 30 to 60 minutes before bedtime is appropriate for men with low-grade prostate cancer.
Those with advanced prostate cancer should consider 20 mg of melatonin. Both suggested dosages have proven to be safe in studies . Clinically, however, I have noticed a few patients reporting a feeling of grogginess in the morning with even low doses of melatonin. To avoid an overdose on melatonin, it is always best to take melatonin and/or any supplement regimen under the supervision of a naturopathic or integrative physician.
As a powerful counter to prostate cancer, not only does melatonin regulate your sleep patterns, it also works very well in alleviating jet-lag symptoms, particularly if taken at bedtime of the arrival destination in healthy men and women .
Modulation Of Immune Responses By Melatonin
The tumor microenvironment is infiltrated by various immune cells. The immune system within the TME has pivotal roles in both inhibition and progression of cancer cells. Natural killer cells and cytotoxic T lymphocytes are the main oncostatic immune cells, while T regulatory cells and cancer-associated fibroblasts facilitate immune escape of cancer cells. Moreover, tumor-associated macrophages release cytokines that attenuate the activity of the immune system against tumor cells or stimulate angiogenesis .
Melatonin exhibits its anticancer effects by modulating the immune system and shifting the immune response toward cancer cells in the TME . For instance, T cells express membrane receptors and nuclear binding sites of melatonin, which could modulate activation and differentiation of T cells. Melatonin stimulates the proliferation of CTLs by increasing the expression level of inflammation cytokines such as IFN-, TNF-, and IL-6 . Melatonin has also been demonstrated to increase the number and activity of CD8+ cytotoxic T cells .
Several studies described the effect of melatonin on Tregs. Melatonin can suppress TGF- and IL-4 and upregulate IFN- to modulate Tregs activity. An animal study showed that 100 mg/kg of melatonin can significantly downregulate the Tregs ratio in a tumor . Patients with an untreatable, metastatic, solid tumor have shown a reduction of Tregs .
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Sleep Melatonin And Cancer
Studies showing connections between poor sleep, low melatonin levels, and cancer have spurred a great deal of interest. Nighttime shift work is linked to fatigue and insomnia, lower levels of melatonin in the blood, and many different illnesses including heart disease, metabolic syndromeand cancers of various types.
Is High Dose Melatonin Dangerous
A report in Medscape states that even 800 mg/kg of body weight was not found to be fatal. Humans given between 1 gm and 6.5 gm per day for 30-45 days produced no negatives when their blood was analyzed.
What Dr. Frank Shallenberger MD says that any reports of side effects of Melatonin are due to the poor quality of the product and artificial additives. He said not to take Melatonin in tablets or liquid with added artificial sweeteners as this can cause some side-effects. Only 100% pure melatonin powder is recommended.
Pure melatonin powder combined with Moringa is an excellent combination for treating cancer. So do not be alarmed if you read reports that Melatonin has been linked to headache, dizziness, nausea, stomach cramps, drowsiness, confusion or disorientation, irritability and mild anxiety, depression and tremors, as well as abnormally low blood pressure and allergies.
Dr. Walter Pierpaoli, one of the worlds leading clinical melatonin researchers, has successfully used daily dosages on mice show even at astronomical doses of 300 mg per day for two years, there were no side effects.Dr. Frank Shallenberger MD who regularly treats cancer patients with similar high doses reports no side effects.
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Melatonin Stops Cancer In Four Different Ways
Cancer is a growing health problem that needs an urgent response to control it. A prediction from the World Health Organizations International Agency for Research on Cancer Global Cancer Observatory expected 27.5 million cancer cases every year by 2040. These values represent a 61.7% increase compared with current statistics. Accordingly, melatonin could be an excellent candidate for the prevention and treatment of several cancers, such as brain cancer, breast cancer, prostate cancer, gastric cancer, and colorectal cancer, etc. The discovery of melatonin in very high doses in cancer treatment is certainly welcome news.
In a Memorial Sloan Kettering review on melatonin with chemotherapy, MST conclude that there is a:
- 40% greater one-year survival
- 93% greater chance of having a complete response
- 253% greater chance of having a partial response
- 15% chance of having stable disease after the combined therapy
- Significantly reduced weakness, fatigue, sickness and lowering of white cell count.
New clinical trials are now progressing.
Melatonin may also decrease risk for and aid treatment of COVID-19 and other RNA viral infections
For estrogen dominant breast cancers and testosterone prostate cancers, melatonin is a key. Melatonin has a direct and an indirect anti-cancer effect. It proves a very pleiotropic effect on cancer. On average, the combined results of these studies show that melatonin reduces the death rate by a whopping 44% . These are from human studies.
Melatonin Inhibits Tumour Growth
As a natural killer, melatonin plays a key role in the uncontrolled growth of cells. Specifically, it reduces the cell division rate, for example by reducing telomerase activity, which results in the programmed cell death of the tumour cells. The researchers also found that melatonin possesses the ability to affect angiogenesis, which is the growth and formation of blood vessels that supply the tumour with oxygen and nutrients, thus facilitating its growth.
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Melatonin In Clinical Trials
Experimental and clinical studies have determined that melatonin exhibits significant prophylactic properties against the toxic adverse event profiles of chemotherapy and radiotherapy . It has also been investigated as a complementary modality alongside chemotherapy owing to its antioxidant and immunoregulatory influences. However, in this capacity, melatonin is still the subject of research and not in use in routine clinical practice . Several studies have documented that melatonin demonstrates a variety of anti-tumor actions. These encompass antioxidant, cytostatic, anti-proliferative, and pro-apoptotic effects, together with various activities pertaining to its ability to regulate epigenetic responses . There are increasing data to show that these anti-malignancy traits are evident during several phases of tumor advancement and dissemination , although recent reports have indicated that these influences are poor or non-existent .
The potentiating influence of melatonin on additional anti-tumor agents requires further elucidation in clinical studies. Moreover, its direct impact, utilizing exogenous administration, on individuals with definitive neoplasia requires further study in order to delineate melatonins effect on tumor progression and to generate its data profile relating to dosage and adverse events. The compounds modes of action also require clarification .
Melatonin Biosynthesis And Metabolism In Human Body
Melatonin was isolated in 1958, by the dermatologist Aaron Lerner, from bovine pineal gland. Although it is mainly secreted from the pineal gland, there are many other secondary sources including retina, gut, skin, platelets and bone marrow, and probably other structures, but their systemic contribution is insignificant .
The starting material of melatonin biosynthesis in humans is tryptophan, an essential amino acid. Through the action of tryptophan hydroxylase and aromatic acid decarboxylase , enzymes tryptophan is converted to the neurotransmitter, serotonin. In the subsequent step, serotonin is converted into melatonin through the influence of arylalkylamine N-acetyltransferase and hydroxyindole-O-methyltransferase enzymes .
Melatonin biosynthesis in human.
Melatonin is metabolized mainly by cytochrome P450 in the liver. It has been demonstrated that melatonin was metabolized to 6-hydroxymelatonin and N-acetylserotonin by CYP1A1 and CYP 2C19, respectively, at Phase I metabolism, and most of them were subsequently converted to sulfate conjugates by sulfotransferases in human liver and excreted in the urine . A small portion of melatonin is degraded by other tissues including skin and brain by either CYPA2B or 2,3-indolamine dioxygenase to form 6-hydroxymelatonin or N1-acetyl-N2-formyl-5-methoxykynurenine . The urinary excretion probably is not the major metabolic route of AFMK judging from its water solubility .
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