Dietary N-acetyl-L-cysteine modulates benzo[a]pyrene-induced skin tumors in cancer-prone p53 haploinsufficient Tg.AC (v-Ha-ras) mice.
Epidemiologic studies support the protective role of dietary antioxidants in preventing cancer. However, emerging evidence from clinical trials and laboratory data suggest that in some cases individual antioxidant supplements may actually exacerbate carcinogenesis. Our goal was to explore these paradoxical activities in a rodent model that possesses genotypic characteristics of human cancers. We selected the p53 haploinsufficient Tg.AC (v-Ha-ras) mouse as a model, because it contains an activated, carcinogeninducible ras oncogene and an inactivated p53 tumor suppressor gene, which are frequent genetic alterations in human cancers. These mice develop chemically induced benign and malignant skin tumors rapidly which can easily be quantified. Mice were fed basal diets with or without 3% N-acetyl-L-cysteine (NAC), a well-recognized antioxidant, prior to, during and after topical application of the carcinogen benzo[a]pyrene (64 microg/mouse) applied twice per week for 7 weeks. Tumor incidence exceeded 90% for both groups, and NAC did not reduce tumor latency. Mice fed NAC displayed a 43% reduction (P < 0.05) in tumor multiplicity and delayed the appearance of lesions (P < 0.05). Dietary NAC also significantly (P < 0.05) improved group survival by 5 weeks. Total tumor yields were reduced in both dietary groups but malignant spindle cell tumors (SCT) increased by 25% in NAC-fed mice. The v-Ha-ras oncogene and p53 protein products were clearly co-expressed in both benign and malignant lesions from both dietary groups. In summary, dietary supplementation with NAC was chemopreventive, but the marginal increase in SCT suggests a paradoxical effect.
Martin
K R
KR
Transgenic Carcinogenesis Unit, Laboratory of Environmental Carcinogenesis and Mutagenesis and Laboratory of Molecular Carcinogenesis, NIEHS, NIH, Research Triangle Park, NC, USA.
Trempus
C
C
Saulnier
M
M
Kari
F W
FW
Barrett
J C
JC
French
J E
JE
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D003043:Cocarcinogenesis; D003433:Crosses, Genetic; D019587:Dietary Supplements; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D000975:Antioxidants; D002273:Carcinogens; D016166:Free Radical Scavengers; D016159:Tumor Suppressor Protein p53; D001564:Benzo(a)pyrene; D000111:Acetylcysteine