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Melatonin And Breast Cancer 2020

Effects Of Melatonin In Cancer

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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.

Role Of Melatonin In Tumor

There are several mechanisms by which tumors evade an immune response including activation of regulatory cells, deformed antigen presentation, immune suppression, and immune deviation . Melatonin has an impact on immune cells by enhancing their viability, improving cell metabolism in the tumor microenvironment, and modulating cytokines release . It was reported that melatonin can stimulate T cell and natural killer production in in vivo study . Liu et al. demonstrated the reduction effect of melatonin on regulatory T cells and Forkhead box p3 in gastric cancer cells . According to Wongsena et al., melatonin has an immunomodulatory effect in hamsters treated with a chemical carcinogen. The results showed that a dose of 50 mg/kg melatonin was able to reduce eosinophils, Th17 cells, and Foxp3 expression, as well as increase CD4+ and TNF- accumulation . Other studies exhibited stimulation of Th1 in tumor-bearing mice treated with melatonin .

Melatonin For Cancer Patients: Is It Safe

If youve ever struggled with insomnia, youve likely heard of melatonin. This nutritional supplement has been widely available in drug stores, health food stores and grocery stores for years, and touted as a natural sleep aid. It even comes in doses meant for children.

But what is melatonin? And is it safe for cancer patients to take during treatment?

We checked in with pulmonologist Saadia Faiz, M.D., for answers.

What is melatonin?

Melatonin is a hormone thats produced naturally by the body. Its secreted by the pineal gland, which is located deep inside the brain. Its thought to help regulate the sleep cycle.

How does melatonin work?

The exact mechanism is not really understood, but melatonin is thought to promote sleep by controlling the circadian rhythm, the natural, 24-hour sleep/wake cycle that many creatures have.

The pineal glands secretion of melatonin is directly tied to the length of the night. Normally, melatonin levels rise as darkness falls, then stay high and steady during the night, and drop again as dawn breaks or people are exposed to bright light.

Where do melatonin supplements come in?

The melatonin in supplements, such as gummies or pills, is usually made in a lab, as opposed to derived from natural sources.

Typically, they are taken a few hours before bedtime. And some clinical studies suggest that melatonin supplements may help users fall asleep more quickly and increase the amount of time they spend asleep.

Is melatonin addictive?

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Lnc049808 Knockdown Inhibited Tnbc Progression

LncRNA microarray analyses were performed with 4T1 and 891 TNBC cells pretreated with melatonin. The results showed that 40 lncRNAs downregulated at least twofold . Among these 40 lncRNAs, we validated the expression levels of the top five downregulated lncRNAs and found that NONMMUT049808 was the sharpest drop after melatonin treatment . Thus, we named this lncRNA lnc049808 and aimed to study it through a series of experiments. shRNA was used to knock down lnc049808 to explore the function of lnc049808 in TNBC progression, and sh-049808#1 produced the highest suppression efficiency and was adopted in subsequent experiments . The CCK-8 assay revealed significant inhibition of cell proliferation by lnc049808 knockdown . lnc049808 knockdown also weakened the cell colony formation ability . The Transwell assay showed that lnc049808 knockdown suppressed cell invasion . To further confirm the role of lnc049808 in vivo, mouse xenograft models were established, and significant inhibition of tumor growth and lung metastasis by lnc049808 knockdown was observed . Our results showed that lnc049808 knockdown inhibited TNBC progression.

Fig. 3: Lnc049808 knockdown inhibited TNBC progression.

Fundc1 Knockdown Inhibited Tnbc Progression


Fig. 1: FUNDC1 knockdown inhibited TNBC Progression.

A 4T1, 891, and BT549 TNBC cells were treated with melatonin or the vehicle for 48 or 96h. B Whole-genome mRNA expression microarray analyses were performed on melatonin-treated and melatonin-untreated 4T1 and 891 cells. C FUNDC1 was upregulated in TNBC tissues compared to normal tissues, according to the TCGA database. D The expression levels of FUNDC1 were determined in breast cancer cell lines by qRT-PCR. White: normal breast epithelial cell line gray: non-TNBC cell line black, TNBC cell line. E qRT-PCR showed that FUNDC1 knockdown was successful with sh-FUNDC1#2. F A CCK-8 assay was performed after transfection in 4T1, 891, and BT549 TNBC cells. G A colony formation assay was performed , and the results were quantified . H A Transwell assay was performed , and the results were quantified . I Representative images of xenograft tumors are shown , and tumor weight was quantified . J H& E-stained sections of metastatic lung nodules are shown , and the number of metastatic nodules was quantified . *p< 0.05, **p< 0.01.

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Urinary Melatonin In Relation To Breast Cancer Risk: Nested Casecontrol Analysis In The Dom Study And Meta

*Corresponding Author:

#N.C. Onland-Moret, T.Y.N. Tong, and R.C. Travis contributed equally as co-last authors of this article.

Corresponding Author:

Cancer Epidemiol Biomarkers Prev 2021 30:97103

Cancer Epidemiol Biomarkers Prev

  • Accepted Manuscript November 3 2020
  • Angel T.Y. Wong, Georgina K. Fensom, Timothy J. Key, N. Charlotte Onland-Moret, Tammy Y.N. Tong, Ruth C. Travis Urinary Melatonin in Relation to Breast Cancer Risk: Nested CaseControl Analysis in the DOM Study and Meta-analysis of Prospective Studies. Cancer Epidemiol Biomarkers Prev 1 January 2021 30 : 97103.

    Melatonin Effect On Proliferative Signaling

    Cancer cells are recognized by their ability to over-proliferate via modulation of protein expression and signaling pathways. The most critical and controlling pathways are hypoxia-inducible factor-1 , NF-B s, PI3K/Akt, insulin-like growth factor receptor , cyclin-dependent kinases , and estrogen receptor signaling .

    Melatonin combined with 5-fluorouracil showed antiproliferation, antimigration, and proapoptotic effects in colon cancer cells by downregulation of PI3K/AKT and NF-B/iNOS signaling pathways . Another study has reported that melatonin inhibited proliferation of CSCs , and reduced protein expression of Ki67 and matrix metalloproteinase 9 . It also prevents cell migration via alteration of PI3K and MAPK signaling pathways in both receptor-dependent and independent manner . Melatonin was able to suppress the cell growth of breast cancer cells in both in vitro and in vivo. The results showed significant downregulation of the HIF-1 gene and protein expression coupled with the production of GLUT1, GLUT3, CA-IX, and CA-XII .

    Furthermore, melatonin has suppressed cell proliferation in human osteosarcoma cells via reducing expression of cyclin D1, CDK4, cyclin B1, and CDK1 .

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    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.

    Experimental Study On Melatonin Use In Glioma/brain Cancer

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    Specifically, recent studies have been conducted on the effect that melatonin supplement with chemo drug Temozolomide can have on malignant gliomas, a cancer of the brain and spinal cord. Experimental studies of combination of melatonin with the chemo Temozolomide showed a synergistic toxic impact on the brain tumor stem cells and A172 malignant glioma cells. Reason for tumor relapse and multidrug resistance in malignant glioma is associated with increased expression of drug transporter proteins that can push the drug out of the cell. Melatonin is able to reduce the expression of these transporters and thus able to help overcome the drug resistance.

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    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 .

    Ethics Approval And Consent To Participate

    Approval for this study was obtained from the Ethics Committee of Sun Yat-Sen University Cancer Center Health Authority and was carried out according to the ethical standards of the Declaration of Helsinki. The IACUC of Sun Yat-Sen University Cancer Center approved all animal studies, which were performed according to its guidelines.

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    Ways To Boost Melatonin Production For Breast Health

    A recent survey found that roughly 50 million Americans suffer from sleep disorders and according to the Centers for Disease Control, insufficient sleep is a public health epidemic. If you have been on a healthy breast journey for some time, you may already know that our body can produce melatonin more effectively when you are in a darkened room.

    But melatonin is not simply for sleep it is a powerful cytotoxic hormone that has many healing properties. Keep reading to learn about the latest research on the healing properties of melatonin as well as 5 SIMPLE ACTIONS you can begin today to keep your melatonin levels up.

    Neuroprotective Effects Of Melatonin In Breast Cancer Patients

    Melatonin And Breast Cancer

    In a clinical trial done by the researchers from the Universidade Federal do Rio Grande do Sul and La Salle University Center in Brazil and Harvard Medical School in the United States, they evaluated the effects of administration of melatonin before and during the first cycle of adjuvant chemotherapy for breast cancer on cognition, depressive symptoms and sleep quality in 36 Breast Cancer Patients . The study found a neuroprotective effect of melatonin to counteract the adverse effects of adjuvant chemotherapy for breast cancer on cognitive function, sleep quality and depressive symptoms.

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    Study Looks At Use Of Melatonin In The Treatment Of Breast Cancer

    A Brazilian study published in the Journal of Pineal Research describes a group of genes potentially regulated by the hormone melatonin in some types of cancer, especially breast cancer.

    Known as the sleep hormone because its functions include regulating the sleep-wake cycle, melatonin has been shown to have anti-tumor properties in laboratory trials. Evidence presented in the scientific literature suggests that low levels of melatonin are associated with a heightened risk of cancer. A possible explanation is that the hormone contributes to the modulation of gene expression and may intensify the activity of tumor suppressor genes, according to the study.

    To identify molecular markers that serve as guides for cancer treatment, the researchers first conducted a study based on meta-analysis to find out how melatonin regulates microRNA expression in breast, head and neck, liver, stomach, prostate, central nervous system, and colorectal cancer.

    Meta-analysis entails a systematic review of the literature using statistical methods to integrate the results of published research on the same subject. MicroRNAs are small RNA molecules that do not encode proteins but perform a regulatory function in the genome, controlling gene expression and hence several cellular processes.

    According to the authors, the results can be used to guide future personalized therapies for the disease.

    Cell Culture And Transfection

    All cell lines used in this study were obtained from the American Type Culture Collection . All cells were cultured according to the suppliers instructions and were confirmed to be free of mycoplasma contamination, as verified by DNA fingerprinting. Cells were transfected with Lipofectamine 2000 . shRNA sequences were synthesized by GeneCopoeia to target Lnc049808 and FUNDC1. A Lenti-Pac HIV Expression Packaging Kit was used to produce lentivirus expressing shRNAs. Puromycin was adopted to select FUNDC1 and Lnc049808 knockdown cells. miR-101 mimics and inhibitors were purchased from GeneCopoeia.

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    Impact Of Melatonin On Survival In Different Cancer Patients

    In a meta-analysis of over 2,754 articles and studies done on the topic, researchers from Qingdao University in China shortlisted 20 randomized clinical trial studies to assess the efficacy of melatonin in cancer therapy. The data spanned between 1992 to 2014. Data from multiple tumor types including 13 lung cancer studies, 11 digestive system tumors, 7 breast cancer studies and 2 studies each of prostate cancer, kidney cancer and melanoma and 1 study each of head and neck cancer and glioma/brain cancer were evaluated for impact of melatonin. The interventions in these studies were melatonin mostly taken at a dosage of 20mg/day orally, taken at night time, combined with their chemo or radiotherapy as the experimental group and chemotherapy alone without melatonin as control group. In this meta-analysis, the authors found that the melatonin group had improvements in tumor remission rates and also a significantly enhanced overall survival rate of 27.98% while compared to the control group of 14.46%. Additionally, they also saw lower chemotherapy side-effects such as neurotoxicity in the melatonin group when compared to the control group. .

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    Microarray And Cluster Analysis

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    The TNBC cell lines 4T1 and 891 were pretreated with melatonin for 24h. Total RNA was extracted with TRIzol reagent . An Affymetrix GeneChip Mouse Genome 430 2.0 Array and Agilent Mouse lncRNA Chip were used for microarray analyses. GeneSpring software V. 13.0 was used for quantile normalization and data processing. Heatmaps were generated with Cluster 3.0 software.

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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 .

    Fundc1 Is A Target Gene Regulated By Mir

    Fig. 2: FUNDC1 Is a Target Gene regulated by miR-101.

    A TargetScan showed the predicted binding sites of miR-101 within FUNDC1. B The expression of miR-101 was detected in breast cancer cell lines. White: normal breast epithelial cell line gray: non-TNBC cell line black, TNBC cell line. C hsa-miR-101 was downregulated in TNBC tissues compared to normal tissues, according to the TCGA database. D The expression level of FUNDC1 after transfection with the miR-101 mimic or LNA-miR-101 was determined by qRT-PCR. E Luciferase assay of cells transfected with vectors containing the FUNDC1 3 UTR or its mutant . F A CCK-8 assay was performed after transfection in 4T1, 891, and BT549 TNBC cells. G A colony formation assay was performed , and the results were quantified . H A Transwell assay was performed , and the results were quantified . I Representative images of xenograft tumors were shown , and tumor weight was quantified . J H& E-stained sections of metastatic lung nodules were shown , and the number of metastatic nodules was quantified . *p< 0.05, **p< 0.01.

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    Lack Of Sleep Also Has A Direct Effect On Breast Cancer Risk Again Due In Large Part To Low Melatonin Levels One Study Conducted Between 2005 And 2008 Compared 1200 Women Who Had Breast Cancer With 1300 Who Did Not The Researchers Found That Women Who Work Night Shifts Had A 30% Incidence Of Breast Cancer

    Those who had done this kind of work for at least four years had the highest risk. Men who work night shifts also have a higher incidence of prostate cancer, according to a 2019 Spanish study among others.

    Another investigation published in the journal Endocrine-Related Cancer found that individuals who worked at night under artificial lights in particular had a high risk for breast cancer. Low melatonin levels, most often caused by lack of sleep, also raise the risk of diabetes and cognitive decline.

    Role Of Melatonin In Tumor Dysregulated Metabolism

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    Cancer cells tend to convert most glucose to lactate, even in the presence of oxygen. This is known as . This pathway enhanced tumor cells to synthesize macromolecules required for rapid cellular proliferation, reduced cell apoptosis, and eventually provided a suitable environment for tumor to metastasis . It was suggested that melatonin stimulate the synthesis of acetyl-CoA from pyruvate by inhibiting the mitochondrial enzyme pyruvate dehydrogenase kinase . A study has shown that melatonin has altered Ewing sarcoma metabolic profile by inhibiting the Warburg effect . In prostate cancer cells, melatonin was able to reduce glucose metabolism via downregulation of glycolysis, tricarboxylic acid cycle, and pentose phosphate pathway .

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