Nicotinamide (NAM), an amide form of niacin (vitamin B3 or vitamin PP), is a precursor of nicotinamide-adenine dinucleotide NAD+ and performs a key role in energy metabolism. It acts in several tissues like skin, nervous system and muscles.

NAM widely affects the nervous system, skin physiology and immune response control. A reduction in NAM levels may lead to serious pathologic conditions such as pellagra.

NAM has recently shown its potential in treating preeclampsia and improving fetal growth. It also decreases the incidence of non-melanoma skin cancers in high-risk individuals. It has shown great results in treating skin conditions like acne vulgaris, melasma, atopic dermatitis, and rosacea. 

Increased risk of diabetes, Parkinson’s disease, and liver damage may be associated with its excessive use; however, it can be used safely at daily doses of up to 3 g. 

The use of NAM in melanoma treatment/prevention has been proposed but not demonstrated. So a group of researchers aimed at investigating NAM antitumor mechanisms of action and addressed its effects in melanoma models both in vitro and in vivo. 

For in vitro investigations-

Human (A375, SK-MEL-28) and mouse (B16-F10) melanoma cell lines were utilized. 

Measurement of - Viability, cell death, cell-cycle distribution, apoptosis, Nicotinamide Adenine Dinucleotide+ (NAD+), Adenosine Triphosphate (ATP), and Reactive Oxygen Species (ROS) levels were done after NAM treatment. 

Testing of- NAM anti-SIRT2 activity was done and the investigation of SIRT2 expression level was done by in silico transcriptomic analyses.

For in vivo investigations-

Melanoma growth measurement was done in- thirty-five C57BL/6 mice injected subcutaneously with B16-F10 melanoma cells and treated intraperitoneally with NAM. 

Counting of- Interferon (IFN)-γ-secreting murine cells were done with ELISPOT assay. 

Measurement of- Cytokine/chemokine plasmatic levels were done by xMAP technology. 

Investigation of- Niacin receptors expression in human melanoma samples was done by in silico transcriptomic analyses.

The observations of the study were as follows-

NAM-

Decreased ~90% melanoma cell number 

It induced: 

1. Accumulation in G1-phase (40% increase),
2. Reduction in S- and G2-phase (about 50% decrease),
3. Increased cell-death (10x) and increased apoptosis in sub-G1 phase (2.5x),
4. Marked increase of NAD+, ATP, and ROS levels,
5. Marked decrease in SIRT2 activity in vitro. 

Markedly delayed tumor growth in vivo

Improved survival of melanoma-bearing mice.

Increased Interferon-gamma (IFN-γ) producing cells (~3-fold) in NAM treated mice. 

significantly changed the plasmatic expression levels of 6 cytokines (namely: Interleukin 5 (IL-5), Eotaxin, Interleukin 12 (p40) (IL12(p40)), Interleukin 3 (IL-3), Interleukin 10 (IL-10) and Regulated on Activation Normal T Expressed and Secreted (RANTES) in the blood of NAM treated mice, proving its role in the immune response. 

Inhibited SIRT2 enzymatic activity 

The authors mentioned that SIRT2 expression is significantly increased in melanoma and inversely related to melanoma-patients survival; and also showed that the expression levels of Niacin receptors HCAR2 and HCAR3 is almost abolished in human melanoma samples.

Thus it was concluded that NAM possesses an anti-melanoma activity in vitro and in vivo and warrants further clinical investigations.

Source: Scatozza, F., Moschella, F., D’Arcangelo, D. et al. Nicotinamide inhibits melanoma in vitro and in vivo. J Exp Clin Cancer Res 39, 211 (2020). https://doi.org/10.1186/s13046-020-01719-3