Melatonin's anti-cancer properties

Melatonin is a hormone that is mainly produced in the mitochondria of all cells in a non-circadian

manner, in response to near-infrared radiation from sunlight, and about 5% is synthesized by the pineal gland at night.{ref}

Melatonin works on many different levels against cancer. {review}

Evening Dosing of Melatonin May Prolong Survival in Non–Small Cell Lung Cancer Patients. Results from a placebo-controlled, randomized, double-blind, 3-arm clinical trial.

"In the nighttime melatonin group, there was a statistically significant (P=0.031) decreased overall survival hazard ratio of 39% compared to the placebo group. The placebo group had a median survival of 10.4 months, whereas the nighttime melatonin group had a median survival of 17.6 months." {ref}

Chronobiological assessment of triple-negative breast cancer. "The study results have shown significant biochemical differences between ER/PR+/ Her2/neu- and TNBC- patients. Reduction of circadian secretion of Melatonin, as a major biochemical marker, directly correlates with the degree of cancer aggression, as it is seen from the study. Furthermore, in patients whose Melatonin concentration was critically low, ductal (CK5/6+ and/or EGFR+) and metaplastic (epidermal: CK5/6+, EGFR+, Ck14+, p63+) forms were histochemically detected, which are extremely aggressive subtypes of TNBC." {ref}

Dose-dependent effect of melatonin on life span and spontaneous tumor incidence in female SHR mice {study} treatment with low dose melatonin (2mg/l for 5 consecutive days every month) significantly decreased spontaneous tumor incidence (by 1,9-fold), mainly mammary carcinomas, in mice whereas higher doses (20mg/l) failed to influence tumor incidence as compared to controls. Guesstimate ≈ 2.43 mg for a 75kg human for the low dose

Melatonin:

reduces OCT4 protein expression.
produces immunomodulatory effects promoting the activity of lymphocytes, monocytes/macrophages, and natural killer cells.{ref}
is a regulator of cell death and inflammation {ref}.
may decrease drug resistance in cancer therapy.
is a HIF-1α inhibitor {ref}.
reduces ammonia 🛈 in the brain {ref}
SIRT1 activator
may suppress ferroptosis (take separately and at least two hours apart from ferroptosis inducers unless it's a synergistic combination {ref|ref}

Melatonin and butyrate 🛈 are two compounds that are mutually beneficial.

Gut dysbiosis and gut permeability decrease butyrate levels and increase LPS levels, favoring the appearance of breast cancer. Melatonin can counteract this effect caused by dysbiosis, preventing breast cancer. Authors: Aurora Laborda-Illanes, Lidia Sánchez-Alcoholado, Soukaina Boutriq, Isaac Plaza-Andrades, Jesús Peralta-Linero,1 Emilio Alba, Alicia González-González, and María Isabel Queipo-Ortuño

Subcellular melatonin signaling is the process by which melatonin is able to act on its target cells and tissues in order to regulate various functions. This process is mediated by a number of proteins called G protein-coupled receptors (GPCRs) which are located on the surface of the cell. When melatonin binds to these GPCRs it activates intracellular signaling pathways which lead to the production of second messengers such as cyclic AMP (cAMP) and calcium ions. These second messengers, in turn, trigger a number of physiological responses in the cell such as changes in gene transcription, protein synthesis, and cell proliferation. By modulating these responses, melatonin is able to regulate various physiological processes in the body.

"Many pathological cells adopt aerobic glycolysis (Warburg effect) in which pyruvate is excluded from the mitochondria and remains in the cytosol where it is metabolized to lactate. The entrance of pyruvate into the mitochondria of healthy cells allows it to be irreversibly decarboxylated by pyruvate dehydrogenase (PDH) to acetyl coenzyme A (acetyl-CoA). The exclusion of pyruvate from the mitochondria in pathological cells prevents the generation of acetyl-CoA from pyruvate. This is relevant to mitochondrial melatonin production, as acetyl-CoA is a required co-substrate/co-factor for melatonin synthesis. When PDH is inhibited during aerobic glycolysis or during intracellular hypoxia, the deficiency of acetyl-CoA likely prevents mitochondrial melatonin synthesis. When cells experiencing aerobic glycolysis or hypoxia with a diminished level of acetyl-CoA are supplemented with melatonin or receive it from another endogenous source (pineal-derived), pathological cells convert to a more normal phenotype and support the transport of pyruvate into the mitochondria, thereby re-establishing a healthier mitochondrial metabolic physiology." {ref}

Synergy

→ Shikonin {ref}
→ DHA docosahexaenoic acid
→ Curcumin
→ Vitamin D3
→ Thymoquinone
→ Andrographis
→ Aloe Vera
→ HDACi 🛈
→ Butyrate {study} 🛈
→ Tamoxifen

Zinc deficiency correlates to decreased melatonin levels.

Supplementation

Labdoor quality rank for Melatonin: Top 30 (don't take it too late at night as you may feel groggy the next day.)
☼ Near-infrared Light (NIR) (go outside during morning/evening light, candlelight, incandescent light, NIR lamps)
Avoid white/blue light after 9PM. If you use the computer after 9PM use f.lux to automatically reduce blue light, and use Blue Blocking Amber Glasses an hour before bedtime.