Dietary N-acetyl-L-cysteine modulates benzo[a]pyrene-induced skin tumors in cancer-prone p53 haploinsufficient Tg.AC (v-Ha-ras) mice

Abstract

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.

Tumor Spectrum in the p53 Heterozygous Zeta Globin-Promoted Tg.AC (v-Ha-ras) Bitransgenic Mouse Model

“…BP administered by the oral gavage route was utilized in this study because it is an extensively studied prototypical polyaromatic hydrocarbon, a complete carcinogen, which hastens the development of proliferative lesions in rodents (Hakura et al, 1998). While BP promoted Tg.AC and p53 genotype-specific changes in the bitransgenic mice in this study it is possible that BP also contributed to those changes which appear to be unique to the bitransgenic mouse (Martin et al, 2001(Martin et al, , 2002Lee et al, 2003). Ras transgene expression is clearly induced in Tg.AC (v-Ha-ras) mice after application of BP as early as 7 weeks with 100% tumor response by eleven weeks supporting our current experimental design (Lee et al, 2003;Martin et al, 2001).…”

“…While BP promoted Tg.AC and p53 genotype-specific changes in the bitransgenic mice in this study it is possible that BP also contributed to those changes which appear to be unique to the bitransgenic mouse (Martin et al, 2001(Martin et al, , 2002Lee et al, 2003). Ras transgene expression is clearly induced in Tg.AC (v-Ha-ras) mice after application of BP as early as 7 weeks with 100% tumor response by eleven weeks supporting our current experimental design (Lee et al, 2003;Martin et al, 2001). BP is more mutagenic in breast tissue than in other organs tested such as liver, lung, and kidney when administered in relatively high doses by gavage as shown in the lacZ mouse (Kosinska et al, 1999).…”

Antigenotoxic and Cancer Preventive Mechanisms of N-Acetyl-l-Cysteine

“…NAC, given at a dosage of 30 g/kg diet, significantly delayed the appearance of skin lesions, reduced tumor multiplicity by 43%, and improved survival by 5 wk. However, malignant spindle-cell tumors were only observed in 25% of NAC-fed mice, and not in controls ( 136).…”

Oxidative DNA Damage Response in Helicobacter pylori-Infected Mongolian Gerbils

“…The level of NAC supplementation (3%, w/w) was adapted from previous study showing the inhibitory effect of NAC against benzo [ α ] pyrene-induced skin tumor. 16 Body weight and food intake were measured every week during the experimental period. There was no difference among groups in body weight and food intake during the experimental periods (data not shown).…”