Role of Nicotinamide in Genomic Stability and Skin Cancer Chemoprevention

Abstract

Nicotinamide (NAM) is an amide form of vitamin B3 and the precursor of nicotinamide adenine dinucleotide (NAD+), an essential co-enzyme of redox reactions for adenosine triphosphate (ATP) production and for other metabolic processes. As NAD+ status is critical in maintaining cellular energy, vitamin B3 deficiency mainly affects tissues that need high cellular energy causing pellagra and skin sun sensitivity. In animal models, NAD+ deficiency leads to UV sensitivity of the skin, impairs DNA damage response, and increases genomic instability and cancer incidence. Furthermore, NAD+ depletion is associated with human skin aging and cancer. NAM prevents the UV-induced ATP depletion boosting cellular energy and enhances DNA repair activity in vitro and in vivo. Moreover, NAM reduces skin cancer incidence and prevents the immune-suppressive effects of UV in mice. Thus, NAM is involved in the maintenance of genomic stability and may have beneficial effects against skin aging changes and tumor development. Clinical studies showed that topical use of NAM reduces cutaneous aging. Furthermore, oral NAM administration reduces the level of UV-mediated immunosuppression and lowers the rate of non-melanoma skin cancers in high-risk patients. Therefore, NAM replenishment strategy may be a promising approach for skin cancer chemoprevention.

The Role of Nicotinamide in Cancer Chemoprevention and Therapy

“…SIRT1 is a NAD + dependent class III histone deacetylase (HDAC) of histones and various non-histone transcription factors (e.g., p53) involved in diverse intracellular processes including DNA repair, metabolism, apoptosis, proliferation, hormone response, aging, and carcinogenesis [39,45,46]. Whereas NAD + stimulates SIRT1-mediated deacetylation of target proteins, low NAD + /NADH ratio diminishes SIRT1 activity [47]. PARP1, triggered by DNA damage (strand breaks), enhances DNA repair and maintains genome stability [40,48].…”

“…PARP1, triggered by DNA damage (strand breaks), enhances DNA repair and maintains genome stability [40,48]. Of interest, mild and moderate genetic damage facilitate DNA repair or apoptosis, respectively; however, severe damage leads to PARP1 overactivation that depletes NAD + and ATP leading to necrosis [40,47]. Notably, while SIRT1 and PARP1 are activated by NAD + and DNA damage, respectively, NAM suppresses both through a negative feedback mechanism ( Figure 1) [38,39].…”

“…Biomolecules 2020, 10, 477 3 of 21 SIRT1-mediated deacetylation of target proteins, low NAD + /NADH ratio diminishes SIRT1 activity [47]. PARP1, triggered by DNA damage (strand breaks), enhances DNA repair and maintains genome stability [40,48].…”

“…In contrast, high oral doses of NAM, especially above 6 g/day, have been associated with gastrointestinal toxicity [40]. Adverse effects such as flushing, hypotension or headache due to vasodilation are believed to be caused by nicotinic acid (another form of vitamin B3, also a NAD + precursor) rather than the NAM itself [39,41,47].…”

“…Actinic keratosis (AK), a common intra-epidermal lesion found in long-term photo-exposed skin areas, increases someone's risk to develop NMSC [84][85][86]; around 10% of AKs are estimated to progress to invasive cancer [87]. Ultraviolet (UV) radiation from sunlight is associated with a higher risk of skin cancer [40,47]. The former depletes NAD + thus ATP and cellular energy; hence, UV-induced DNA damage is followed by defective DNA repair and genetic instability [40,47].…”