Background
What is melatonin?
A hormone primarily produced by the pineal gland that regulates circadian rhythms.
What type of studies made up the majority of the evidence for outcome 1 (tumour progression)?
Preclinical studies (in vitro and animal)
What is Glioblastoma?
GBM is an aggressive and highly malignant primary brain tumor.
In normal/healthy cells, what is the redox role of melatonin?
It acts as an antioxidant
Is a prescription required to buy melatonin in Canada?
No, melatonin is sold over the counter without a prescription.
When is melatonin primarily secreted in humans?
During darkness / at night.
What was the main limitation of the human evidence for tumour progression?
Lack of high-quality RCTs directly measuring tumour progression.
What are YTS-1, T24, and J82?
Human cell lines injected with varying concentrations of melatonin in the in vitro experiments
This metabolic effect names the phenomenon where cancer cells primarily use aerobic glycolysis for energy production
What is the Warburg Effect.
What melatonin dose is commonly used in cancer trials
10-20mg/day
Which gland is the primary source of melatonin production?
The pineal gland.
What pattern did observational studies consistently show regarding melatonin levels and cancer outcomes?
Lower melatonin levels were associated with higher cancer risk or more aggressive disease.
Why did the study use xenograft mouse models instead of normal healthy mice?
To study the effects of melatonin when it was used in combination with other cancer drugs on tumor cells.
Which immune cells does melatonin help reduce the activity of in order to re-sensitise the immune system?
T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs).
Melatonin sold in stored is approved to treat cancer. True or false? and why?
False. Melatonin sold in stores is not approved to treat cancer, and in none of the labels is mentioned anything cancer related. The doses are also too small to affect.
Why might melatonin be relevant in cancer patients?
Because cancer and its treatments often disrupt circadian rhythms.
Why does Outcome 1 (tumour progression) have weaker supporting evidence than Outcome 2 (sensitization)?
Outcome 1 relies mostly on preclinical and observational evidence, which made it more susceptible to confounding and not directly causal, whereas outcome 2 includes RCTs/meta-analyses that more directly test cause-and-effect in humans.
What is O-GlcNAcylation?
A post-translational modification that is associated with cancer cells and melatonin was found to inhibit.
Why is melatonin selectively pro-oxidative in tumour cells?
Because they have an altered tumour environment with Warburg metabolism, which makes the more susceptible to ROS mediated DNA damage.
What must all melatonin products legally sold in Canada display on their packaging to indicate Health Canada approval?
A Natural Product Number (NPN).
Why is melatonin considered suitable for adjunct research in cancer?
Because of its low toxicity and systemic biological effects.
What is the biggest reason observational findings in outcome 1 cannot be interpreted as proof that melatonin causes improved cancer outcomes?
Observational studies don’t establish causation relations + confounding factors and heterogeneity exists more extensively in observational studies.
What is a setback with in-vivo and in-vitro study design?
The administration and dosages of melatonin in the studies are not feasible for the average person.
Two patients receive melatonin as adjuvant therapy. For patient A, melatonin is supplemented alongside Cisplatin, and Patient B gets melatonin with Capivasertib, an AKT inhibitor. Based on this presentation, which patient would you expect to benefit more?
Patient A: Cisplatin acts on DNA damage induced by ROS, and therefore would be more effective in adjuvant with melatonin.
Experimental studies show melatonin can?
Slow cancer cell growth, trigger cancer cell death (apoptosis), and limit blood vessel formation and metastasis.