A Randomized Controlled Trial of Topical 5% Niacinamide for Skin Cancer Prevention in Transplant Recipients

Background, Significance, and Preliminary Studies

Organ transplant recipients (OTRs) have at least a 50 times higher risk of developing non-melanoma skin cancers than the general population (Moloney et al., 2006). These skin cancers in OTRs also tend to be more aggressive, with higher rates of recurrence and metastasis (Martinez et al., 2003). Immunosuppression in OTRs is primarily achieved through the use of pharmacologic agents such as mycophenolate mofetil, azathioprine, cyclosporine, and tacrolimus, among other medications. These agents work by inhibiting various components of the immune system to prevent graft rejection. For instance, calcineurin inhibitors like cyclosporine and tacrolimus inhibit T-cell activation by blocking the production of interleukin-2 (IL-2), a critical cytokine for T-cell proliferation. Mycophenolate mofetil and azathioprine inhibit purine synthesis, thereby reducing lymphocyte proliferation. These immunosuppressive drugs, while effective in preventing rejection, also impair DNA repair mechanisms and immune surveillance and increase the risk of malignancies, particularly skin cancers.

Nicotinamide (NAM), the amide derivative of vitamin B3, has been investigated for its potential role in reducing the incidence of skin cancer. Ultraviolet (UV) radiation exposure in the absence of NAM results in a significant reduction in cellular adenosine triphosphate (ATP) levels. NAM has been shown to enhance DNA repair mechanisms and mitigate UV-induced immunosuppression by preserving cellular ATP levels (Park et al., 2010). In the context of oncogenesis, the maintenance of ATP levels is commonly associated with the promotion of antitumor immune responses, whereas elevated levels of extracellular adenosine (ADO) are often seen in cancer. The ectonucleotidase CD39 catalyzes the rate-limiting step in the hydrolysis of extracellular ATP to extracellular ADO. Work by Whitley et al. (2021), employing a murine model, demonstrated that CD39 expression on skin-resident T cells regulates DNA damage repair through ATP-mediated signaling pathways. Taken together, these findings suggest a mechanistic pathway by which NAM may exert chemopreventive effects. NAM appears to maintain cellular ATP levels, which facilitates DNA repair and supports antitumor immunity through the modulation of extracellular ATP and adenosine (ADO) signaling.

Several other potential mechanisms by which NAM may be chemoprotective are described in the literature. In human keratinocyte cultures, tumor protein p53 (TP53), a key protector of the DNA damage response, was significantly upregulated following UV exposure in the presence of NAM when compared to UV exposure without NAM (Sirapivabu et al., 2009). TP53 is often referred to as the guardian of the genome and its loss is observed in many cancers. Further, keratinocytes treated with NAM and exposed to UV radiation and arsenic demonstrated protection against cyclobutane pyrimidine dimer (CPDs) and 8-oxo-7,8-dihydro-2'-deoxyguanosine formation, which are DNA photolesions (Damian et al., 2015). Photolesions can result in carcinogenic mutations if not repaired. NAM has also been shown to facilitate repair of such photolesions through multiple pathways (Surjana et al., 2013).

While oral NAM has shown promise in skin cancer prevention, clinical trials in high-risk patients have yielded mixed results. A phase 3 randomized controlled trial by Chen et al. (2015) of 386 high-risk immunocompetent patients demonstrated that oral nicotinamide (500 mg twice daily for 12 months) significantly reduced the rate of new nonmelanoma skin cancers (NMSCs) by 23% (P = 0.02) compared to placebo. Reductions were observed for new squamous cell carcinomas (30% reduction, P = 0.05) and basal cell carcinomas (20% reduction, P = 0.12), and actinic keratoses counts were significantly lower throughout treatment (P < 0.001 at multiple time points). A pilot double-blind randomized trial in renal transplant patients by Chen et al. (2016) evaluated oral nicotinamide (500 mg twice daily) for prevention of nonmelanoma skin cancers (NMSCs) and actinic keratoses (AKs). Over 6 months, nicotinamide showed a nonsignificant 35% relative reduction in NMSC rate (P = 0.36) and a 16% reduction in AKs (P = 0.15) compared to placebo. A study by Hwang et al. (2025) utilized a retrospective cohort study design to evaluate the effect of oral nicotinamide supplementation in a group of 47 OTRs. It was demonstrated that nicotinamide 500 mg twice daily for at least a year decreased the incidence of KCs at one and two year follow up (Hwang et al., 2025).