Vitamin B Derivative (Nicotinamide) Appears to Reduce Skin Cancer Risk

Safia Nazarali, MSc and Paul Kuzel, MD, FRCPC

University of Alberta, Faculty of Medicine and Dentistry, Edmonton, AB, Canada

Conflicts of Interest:
The authors have no conflicts to disclose.

ABSTRACT
Nicotinamide, an amide form of vitamin B3, has shown the potential to treat a variety of dermatological conditions, including acne, rosacea, and atopic dermatitis. Recent studies have demonstrated the role of nicotinamide, in both topical and oral forms, as a chemopreventive agent against skin cancer. Its anti-carcinogenic role may be due to its ability to enhance DNA repair and prevent ultraviolet (UV)-induced immunosuppression, which is known to contribute to the progression of pre-malignant lesions. Furthermore, nicotinamide is a precursor of essential coenzymes for many important reactions in the body, including the production of nicotinamide adenine dinucleotide (NAD). NAD is a key coenzyme in the synthesis of adenosine triphosphate (ATP), which transports chemical energy within cells. Therefore, nicotinamide plays a significant role in supporting energy-dependent cellular processes, including DNA repair.

Key Words:
vitamin B, nicotinamide, skin cancer, chemoprevention

Introduction

Nicotinamide is an amide form of vitamin B3. The other main form of vitamin B3 is niacin (Figure 1). Vitamin B3 is an essential water-soluble vitamin. It is not stored in the body, and is maintained by dietary intake of both vitamin B3 and tryptophan. Tryptophan is an essential amino acid found in most forms of protein.¹ Vitamin B3 is found in foods such as legumes, nuts, grain products, mushrooms, chicken, pork, beef and fish.² The recommended daily intake of niacin for men and women is 16 mg and 14 mg, respectively; this dose increases to 18 mg during pregnancy and 17 mg for lactating women.³ Diets deficient in vitamin B3 can result in a condition known as pellagra, which is characterized by diarrhea, dermatitis, dementia and death (the 4 D’s).⁴

Both vitamin B3 derivatives, niacin and nicotinamide, are precursors for the production of nicotinamide adenine dinucleotide (NAD), which is a key coenzyme in the synthesis of adenosine triphosphate (ATP).⁵ Since ATP is responsible for transporting chemical energy within cells, nicotinamide and niacin play a significant role in boosting cellular energy and supporting many energy-dependent cellular processes, such as DNA repair.¹ Nicotinamide has been shown to prevent the depletion of cellular NAD levels, which occurs as a result of ultraviolet (UV) exposure.⁶ Decreased NAD levels are associated with increased susceptibility to cell genotoxicity, indicating that there is an inverse relationship between cellular NAD concentration and susceptibility to DNA damage.⁵ A study conducted by Gensler et al. (1999) demonstrated that in mice there is an inverse relationship between niacin supplementation and UV-induced skin cancer susceptibility due to niacin’s role in increasing cellular NAD levels.⁷ The findings of the study showed that dietary supplementation with 0.1%, 0.5% or 1.0% niacin reduced the incidence of skin cancer from 68% to 60%, 48% and 28%, respectively. These results demonstrate a dosedependent reduction in skin cancer risk with the use of niacin supplementation.

Cellular Mechanisms

Nicotinamide and PARP-1

One mechanism by which cellular NAD levels influence responses to DNA damage involves the consumption of NAD for the synthesis of adenosine diphosphate (ADP)-ribose polymers and cyclic ADP-ribose, both of which are critical for apoptosis and necrosis.⁵ In addition, NAD is the single known substrate and inhibitor of the nuclear enzyme poly-ADP-ribose polymerase-1 (PARP-1).5 PARP-1, shown to be activated by UV radiation, plays a significant role in DNA repair and genomic stability.⁵ It does so by regulating transcription factors that are associated with the expression of inflammatory cytokines, chemokines, adhesion molecules and inflammatory mediators.⁸ Both PARP-1 and NAD influence cellular responses to genotoxicity and, as a result, may prevent mutagenesis and cancer formation.

Nicotinamide and Sirtuins

Sirtuins, NAD-dependent enzymes, play a key role in cellular responses to environmental stressors.⁹ Their effect on various transcription factors, including the tumor suppressor protein p53, contributes to their role in modulating cell metabolism and regulating cell survival.⁹ Sirtuin gene expression is triggered by UV irradiation. Actinic keratosis (AK) and squamous cell carcinoma (SCC) lesions show an upregulation of sirtuin gene expression, indicating that sirtuin may be associated with early stages of skin cancer formation.⁹ Nicotinamide inhibits sirtuin activity, which likely contributes to its protective effect against UV mutagenesis.⁹

Nicotinamide and DNA Repair

Nicotinamide plays an important role in DNA repair due to its function as an NAD precursor and as a substrate for PARP-1.¹⁰ PARP-1 is involved in several DNA damage responses, including DNA repair, maintenance of genomic stability, transcriptional regulation, signaling pathways involved in apoptosis, and telomere functions.¹⁰ As can be seen in Figure 2, nicotinamide and niacin are key components of NAD synthesis. This, in turn, is essential for ATP production and the activation of PARP-1. DNA strand breaks result in the activation of PARP-1, cleaving NAD into nicotinamide and ADP-ribose.⁵

The activation of PARP-1 by DNA strand breaks can activate 3 different cellular pathways, depending on the severity of DNA damage. When DNA damage is mild, PARP-1 activation enhances DNA repair by interacting with p53, signaling cell cycle arrest and facilitating DNA repair enzymes.5 Irreparable DNA damage causes PARP-1 activation to lead to apoptotic cell death by preventing ATP depletion and DNA repair through caspase-mediated PARP-1 cleavage. Finally, severe DNA damage leads to the overactivation of PARP-1. This causes NAD depletion and a cellular energy crisis as cells consume ATP in an attempt to replenish depleted NAD stores. The result is necrotic cell death.

UV radiation (from both UVA and UVB exposure) is the primary cause of skin cancer. UVB exposure damages DNA, which results in the formation of cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs).11 CPDs lead to signature C to T and CC to TT transition mutations. UVA exposure also induces CPDs, but causes singlet oxygen photosensitization-induced DNA photolesions including 8-oxo- 7,8-dihydro-2′-deoxyguanosine (8oxoG).11 In 2013, Surjana et al. conducted a study to observe nicotinamide’s effect on DNA repair following UV irradiation. The results showed that nicotinamide increases DNA excision repair activity in immortalized human keratinocytes (HaCaT cells) and enhances the repair of CPDs and 8oxoG following the exposure of human keratinocytes and ex vivo human skin to solar-stimulated UV.11 This may contribute to nicotinamide’s apparent chemoprotective effects against skin cancer. Further evidence to support nicotinamide’s chemoprotective effects is that, under conditions of NAD depletion, human HaCaT keratinocytes showed increased DNA damage, even if genotoxic stressors were not present.12 The addition of nicotinamide to the NAD-depleted cell cultures reversed this effect.

Nicotinamide and Immunosuppression

UV radiation, even in small doses, can cause immunosuppression, which contributes to the development of skin cancer by impairing the immunosurveillance of DNA damage.¹³ Sivapirabu et al. (2009) conducted a randomized, double-blinded study involving 70 healthy participants to show that topical nicotinamide (5%) prevents UV-induced immunosuppression.¹⁴ Skin immunity was determined by the Mantoux reaction, which measures the erythemal component of the delayed-type hypersensitivity response. The results showed a reduction of immunosuppression by approximately 50% after both single and multiple UV exposures. Similar results were found when the study was repeated using a much lower dose of topical nicotinamide (0.2%). Another study conducted by Damian et al. (2008) showed that applying 5% topical nicotinamide 3 days before solar-simulated UV exposure significantly suppressed Mantoux reactions.¹⁵ Based on this evidence, topical nicotinamide is effective at preventing UV-induced immunosuppression, whether it is applied prior to or after UV exposure.

Oral nicotinamide has also been shown to be effective in protecting against UV-induced immunosuppression. A randomized, placebo-controlled study using 30 healthy Mantouxpositive participants showed that 500 mg of oral nicotinamide taken 3 times daily for 7 days significantly reduced UVinduced immunosuppression.¹³ The study was repeated with 31 participants using a once daily dose of 500 mg oral nicotinamide. The results showed that the lower dose was equally as effective in reducing UV-induced immunosuppression.¹³

Clinical Evidence

Numerous studies have demonstrated the ability of nicotinamide to decrease the incidence of new nonmelanoma skin cancers (NMSCs) and AKs in susceptible individuals. Kim et al. (2015) combined the results of 2 randomized, double-blinded phase 2 trials that examined the effect of oral nicotinamide on AK counts in individuals with photo-damaged skin.¹⁶ Seventy-four patients were enrolled in the 2 trials (37 in the placebo group and 37 in the nicotinamide group). Approximately 81% of participants in the placebo group and 79% of participants in the nicotinamide group had previous skin cancers; 11 patients developed a total of 20 new skin cancers at 4 months in the placebo group, while 2 patients developed a total of 4 new skin cancers at 4 months in the nicotinamide group. The results demonstrated a significant reduction in the odds of developing at least 1 skin cancer with the use of nicotinamide in comparison to placebo (p=0.019).

A recent phase 3 randomized, double-blind, controlled trial conducted by Chen et al. (2015) recruited 386 patients who had been diagnosed with at least 2 NMSCs, specifically basal cell carcinomas (BCCs) plus SCCs, in the previous 5 years.¹⁷ The participants were randomized in a 1:1 ratio to receive either 500 mg nicotinamide twice daily or placebo for 12 months. Dermatologists evaluated participants at 3-month intervals for the 12-month trial period, as well as for 6 months after the intervention period. The primary endpoint of the trial was the number of new NMSCs during the 12-month intervention period. Secondary endpoints included the number of new BCCs, SCCs, and AKs during the 12-month period, the number of NMSCs in the 6-month post intervention period and the safety of nicotinamide. The results of the trial showed a 23% reduction in the rate of NMSCs in the nicotinamide group compared to the placebo group at 12 months (p=0.02). Similar results were found for the rate of BCCs and SCCs (20% and 30% lower in the nicotinamide group than in the placebo group, respectively). The number of AKs was also found to be lower in the nicotinamide group than in the placebo group at 3 months, 6 months, 9 months, and 12 months. The trial reinforced the safety profile of nicotinamide by showing no between-group differences with regards to the number or types of adverse events during the intervention period.

Other Skin Conditions

Nicotinamide has also shown to be beneficial in treating various dermatological skin conditions, including acne and rosacea. In addition, used together with corticosteroids, it is commonly prescribed for inflammatory autoimmune conditions like bullous pemphigoid and pemphigus.¹⁸

Acne Vulgaris

Acne vulgaris is one of the most common skin conditions for which patients seek dermatologic care.¹⁹ Factors contributing to acne vulgaris include sebum production, bacterial growth, and associated inflammation.¹⁹ Nicotinamide has anti-inflammatory, sebo-suppressive, and healing properties, which have shown benefit for acne vulgaris when used topically. A study of 50 Japanese participants treated with 2% topical nicotinamide showed significantly lowered sebum excretion rates after 2 and 4 weeks of application.¹⁹ An earlier double-blind trial by Shalita et al. (1995) involved 76 participants with moderate inflammatory acne.²⁰ The results demonstrated that 4% topical nicotinamide gel and 1% clindamycin gel were statistically similar in decreasing acne symptoms over an 8-week period. From the participants treated, 82% showed improvement in acne symptoms.

Rosacea

Rosacea is a chronic facial dermatosis, characterized by the presence of erythema, papules, pustules, telangiectasias and sebaceous gland hyperplasia.²¹ Wozniacka et al. (2005) treated 34 patients with rosacea using a gel containing 0.25% N-methylnicotinamide (a metabolite of nicotinamide) for 4 weeks.²¹ The results indicated a good to moderate improvement in rosacea in 76% of participants. After 2 weeks of use, the majority of patients experienced a 50-75% reduction in the appearance of erythema and papules.²¹

Aging Skin

Nicotinamide also improves the appearance of aging skin.²² A double-blind randomized controlled trial with 50 Caucasian female participants observed the effect of topical nicotinamide on the appearance of photo-aged skin.²² Participants used 5% nicotinamide cream on their faces for 12 weeks. The results showed a significant improvement in skin appearance, including reductions of fine lines and wrinkles, hyperpigmented spots, red blotchiness and skin sallowness, as well as improved elasticity.

Inflammatory Autoimmune Conditions

Nicotinamide has shown to be an effective treatment for a variety of autoimmune conditions, particularly autoimmune blistering disorders. Nicotinamide, in combination with tetracycline, inhibits neutrophil and eosinophil chemotaxis, resulting in inhibition of the humoral immune response.²³ Thus, the combination of these two drugs has been shown to be an effective treatment in patients with bullous pemphigoid.²³ Nicotinamide has also been demonstrated to be a beneficial adjunctive therapy for patients with pemphigus vulgaris. A study conducted by Iraji and Banan (2010) showed that nicotinamide gel, applied topically, is an effective alternative to corticosteroids for treating pemphigus vulgaris lesions.²⁴

Conclusion

Nicotinamide is a widely available, inexpensive and welltolerated agent. It has been reported in a small number of studies to be of benefit in a range of skin conditions, including acne, rosacea, immunobullous disease and photoaging. Recent studies show that it may also be an effective chemopreventive agent against skin cancer, possibly due to its ability to both augment cellular DNA-repair mechanisms and counteract UVinduced immunosuppression. Due to its favorable safety profile and demonstrated effectiveness, nicotinamide supplementation should be considered as an adjunctive chemopreventative treatment for patients at high risk of developing NMSC or AKs.

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