title: Niacin status and genomic instability in bone marrow cells; mechanisms favoring the progression of leukemogenesis.
abstract: Niacin deficiency causes dramatic genomic instability in bone marrow cells in an in vivo rat model. The end result is seen in the increased incidence of sister chromatid exchanges, micronuclei, chromosomal aberrations and the eventual development of nitrosourea-induced leukemias. From a mechanistic perspective, niacin deficiency delays excision repair and causes double strand break accumulation, which in turn favor chromosome breaks and translocations. Niacin deficiency also impairs cell cycle arrest and apoptosis in response to DNA damage, which combine to encourage the survival of cells with leukemogenic potential. Niacin deficiency also enhances the level of oxidant damage found in cellular proteins and DNA, but not through depression of GSH levels. Pharmacological supplementation of niacin decreases the development of nitrosourea-induced leukemias, while short term effects of high niacin intake include a large increase in cellular NAD+ and poly(ADP-ribose) content and enhanced apoptosis. These results are important to cancer patients, which tend to be niacin deficient, are exposed to large doses of genotoxic drugs, and suffer short-term bone marrow suppression and long-term development of secondary leukemias. The data from our rat model suggest that niacin supplementation of cancer patients may decrease the severity of short and long-term side effects, and may also improve tumor cell killing through activation of poly(ADP-ribose)-dependent apoptosis pathways.
authors: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1, jkirklan@uoguelph.ca.
authors: James B
authors: JB
authors: Kirkland
mesh_terms: D000818:Animals; D001361:Avitaminosis / Q000473:pathology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D042822:Genomic Instability / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000209:etiology*; D009525:Niacin / Q000008:administration & dosage / Q000172:deficiency*; D009752:Nutritional Status; D051381:Rats; D015398:Signal Transduction
chemical_list: D009525:Niacin