Suppression of spontaneous and hydrogen peroxide-induced mutagenesis by the antioxidant ascorbate in mismatch repair-deficient human colon cancer cells.
Genomic instability associated with deficiencies in mismatch repair (MMR) plays a critical role in tumorigenesis. Here we have investigated the contribution of oxidative damage to this instability in MMR-defective cells. Treatment with H(2)O(2) produced less cytotoxicity in MMR-deficient cells than in those proficient in MMR, supporting a role for MMR in the recognition and/or processing of oxidative damage. Additionally, growth of MMR-defective cells in the presence of the antioxidant ascorbate (500 microM) reduced the spontaneous mutation rate at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus by up to 50% and reduced microsatellite instability by 30%. Induction of HPRT mutants by exogenously added H(2)O(2) was also significantly suppressed by ascorbate. Collectively, these results suggest that (i) oxidative damage contributes significantly to the spontaneous mutator phenotype in MMR-defective cells, (ii) this damage may select for MMR-deficient cells due to their increased resistance to cell killing and (iii) dietary antioxidants may help to suppress the mutator phenotype and resulting carcinogenesis in individuals with compromised MMR.
Glaab
W E
WE
Department of Genetic and Cellular Toxicology, Merck Research Laboratories, WP45-320, West Point, PA 19486, USA. warren_glaab@merck.com
Hill
R B
RB
Skopek
T R
TR
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D020137:Base Pair Mismatch; D002470:Cell Survival / Q000187:drug effects; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000517:prevention & control*; D004260:DNA Repair / Q000502:physiology*; D016166:Free Radical Scavengers; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D018895:Microsatellite Repeats; D016296:Mutagenesis / Q000187:drug effects*; D009152:Mutagenicity Tests; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D013866:Thioguanine / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D000975:Antioxidants; D016166:Free Radical Scavengers; D009363:Neoplasm Proteins; D006861:Hydrogen Peroxide; D007041:Hypoxanthine Phosphoribosyltransferase; D013866:Thioguanine; D001205:Ascorbic Acid