Liver tumors were induced in male C3H mice by a single injection of N-nitrosodiethylamine and characterized with respect to the presence of base substitutions in the hot-spot position at codon 61 of the Ha-ras proto-oncogene. An increase in Ha-ras mutation prevalence was found with time after induction of tumors, suggesting that the activated ras gene provides a selective growth advantage. However, no significant differences in 5-bromodeoxyuridine labeling indices were evident between ras mutated and ras wild-type tumors, demonstrating that cell division rates in the two tumor populations were very similar. Apoptotic indices were determined by counting eosinophilic apoptotic bodies. The frequency of occurrence of apoptotic bodies was found to be approximately five times lower in tumors with Ha-ras mutations when compared with tumors not showing the mutation. This demonstrates that the activated p21(Ras) protein has anti-apoptotic activity in transformed mouse hepatocytes in vivo and suggests that the preferential outgrowth of Ha-ras-mutated hepatoma cells is mediated by suppression of apoptosis rather than by stimulation of cell division.
Taraxacum officinale (TO), the common dandelion, has been used traditionally as a diuretic and as a treatment for jaundice and other liver disorders. Recent studies have substantiated its diuretic effect; in addition, it exhibits considerable antimicrobial, anti-inflammatory, antioxidant, hypolipidemic, and anti-breast and anti-prostate cancer-cell properties. In this study, the effects of TO as a chemopreventive agent of early-stage colon cancer development were evaluated. In the in vivo investigation, C57BL/6 mice between 6–10 wk old were randomized into negative control (N = 10), positive control (N = 10), and experimental (N = 10) groups. Aberrant crypt foci (ACF), putative precursors of colon cancer, were induced in positive control and experimental mice by intraperitoneal injection of azoxymethane (AOM; 5 mg/kg body mass) at the beginning of the first and second weeks, while the negative control mice received none. The experimental group was daily fed TO extract (1 mL/mouse; 84.22 mg/mL) by gavage throughout the duration of the 8-wk study while the control groups received a sterilized-water placebo. Mice in all three groups were sacrificed at the end of the 8-wk period and 25 mm of the proximal colon were resected and analyzed for ACF development after staining with methylene blue. Histological preparations of the proximal colon samples were used to determine apoptotic index, mitotic index, and caspase induction. Oral TO administration significantly reduced the number of AOM-induced ACF in the proximal colon in the experimental group in comparison to the positive control group (10.67 ± 3.75 < 32.10 ± 9.86; P < 0.00016), which indicates a 68.9 % inhibition of ACF formation by TO and a potency index of 3.01. The mice in all three groups experienced weight gain (negative: 7.0% < positive: 7.5% < experimental: 8.1%). Colon samples from the experimental group revealed a higher apoptotic index (AI) (1.34 > 0.60; P < 0.0002) and a lower mitotic index (MI) (1.13 < 2.80; P < 0.25) than the positive control group (AOM only). Caspase 3 and 9 induction was detected in human colorectal carcinoma HCT-116 cells treated with TO (.05 mg/mL) in chamber slides, using a specific carboxyfluorecein (FAM) labeled peptide fluoromethyl ketone (FMK) caspase inhibitor (FAM-peptide-FMK). Caspase 3 and 9 activation was also observed in TO-treated mouse colon tissues using the same caspase inhibitor. The data suggests that TO possesses potential chemopreventive effects on colon cancer development through the inhibition of AOM-induced ACF formation via C3/C9-regulated apoptosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-21. doi:10.1158/1538-7445.AM2011-LB-21
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