Topical nicotinamide (niacinamide) has demonstrable preventive activity against photocarcinogenesis in mice. To better understand how this vitamin prevents ultraviolet (UV) carcinogenesis, we tested systemic administration of another form of the vitamin, niacin, and its capacity to elevate cutaneous nicotinamide-adenine dinucleotide (NAD) content as well as to decrease photoimmunosuppression and photocarcinogenesis. BALB/cAnNTacfBR mice were fed the AIN-76A diet supplemented with 0%, 0.1%, 0.5%, or 1.0% niacin throughout the experiment. UV irradiation consisted of five 30-minute exposures per week to banks of six FS40 Westinghouse sunlamps for 22 weeks in the carcinogenesis experiments, yielding a total cumulative dose of approximately 1.41 x 10(6) Jm-2 of UV-B radiation. Dietary supplementation with 0.1%, 0.5%, or 1.0% niacin reduced the control incidence of skin cancer from 68% to 60%, 48%, and 28%, respectively, at 26.5 weeks after the first UV treatment. Two potential mechanisms by which niacin prevents tumor formation were identified. Photoimmunosuppression, critical for photocarcinogenesis, is measured by a passive transfer assay. Syngeneic, antigenic tumor challenges grew to an average of 91.6 +/- 19.7, 79.8 +/- 11.5, 41.9 +/- 11.7, or 13.2 +/- 4.1 mm2 in naive recipients of splenocytes from UV-irradiated mice treated with 0%, 0.1%, 0.5%, or 1.0% niacin supplementation, respectively, demonstrating niacin prevention of immunosuppression. Niacin supplementation elevated skin NAD content, which is known to modulate the function of DNA strand scission surveillance proteins p53 and poly(ADP-ribose) polymerase, two proteins critical in cellular responses to UV-induced DNA damage. These results clearly demonstrate a dose-dependent preventive effect of oral niacin on photocarcinogenesis and photoimmunosuppression and establish the capacity of oral niacin to elevate skin NAD levels.

DNA double-strand breaks, the most serious DNA lesion caused by ionizing radiation, are also caused by several vitamin or mineral deficiencies, such as for folate. Primary human lymphocytes were either irradiated or cultured at different levels of folate deficiency to assess cell proliferation, apoptosis, cell cycle, DNA breaks, and changes in gene expression. Both radiation and folate deficiency decreased cell proliferation and induced DNA breaks, apoptosis, and cell cycle arrest. Levels of folate deficiency commonly found resulted in effects similar to those caused by 1 Gy of radiation, a relatively high dose. Though both radiation and folate deficiency caused DNA breaks, they affected the expression of different genes. Radiation activated excision and DNA double-strand break repair genes and repressed mitochondrially encoded genes. Folate deficiency activated base and nucleotide excision repair genes and repressed folate-related genes. No DNA double-strand break repair gene was activated by folate deficiency. These findings suggest that a diet poor in folate may pose a risk of DNA damage comparable to that of a relatively high dose of radiation. Our results also suggest that research on biological effects of low-dose radiation should take into account the nutritional status of the subjects, because folate deficiency could confound the effects of low-dose radiation.

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Studies presented here show that cellular NAD, which we hypothesize to be the relevant biomarker of niacin status, is significantly lower in humans than in the commonly studied animal models of carcinogenesis. We show that nicotinamide and the resulting cellular NAD concentration modulate expression of the tumor suppressor protein, p53, in human breast, skin, and lung cells. Studies to determine the optimal NAD concentrations for responding to DNA damage in breast epithelial cells reveal that DNA damage appears to stimulate NAD biosynthesis and that recovery from DNA damage occurs several hours earlier in the presence of higher NAD or in cells undergoing active NAD biosynthesis. Finally, analyses of normal human skin tissue from individuals diagnosed with actinic keratoses or squamous cell carcinomas show that NAD content of the skin is inversely correlated with the malignant phenotype. Since NAD is important in modulating ADP-ribose polymer metabolism, cyclic ADP-ribose synthesis, and stress response proteins, such as p53, following DNA damage, understanding how NAD metabolism is regulated in the human has important implications in developing both prevention and treatment strategies in carcinogenesis.