Prevention of liver carcinogenesis by Amarogentin through modulation of G1/S cell cycle check point and induction of apoptosis
Menée sur un modèle murin exposé au tétrachlorure de carbone et au N-Nitrosodiéthylamine, cette étude montre que l'amarogentine, un glycoside seco-iridoïde provenant de la plante Swertia chirata (famille de la gentiane), peut inhiber la carcinogenèse du foie en agissant sur les processus de régulation du cycle cellulaire et de l'apoptose
Amarogentin a secoiridoid glycoside is an active component of the medicinal plant Swertia chirata. In this study chemopreventive and chemotherapeutic action of amarogentin was evaluated in a Carbon tetrachloride (CCl4)/ N-nitrosodiethylamine (NDEA) induced liver carcinogenesis mouse model system during continuous and post treatment schedule. Better survival, no toxicity and increased body weight were noted in amarogentin treated mice. Reduction in proliferation and increase in apoptosis frequency were evident in amarogentin treated groups. In carcinogen control group moderate dysplasia, severe dysplasia and hepatocellular carcinoma (HCC) were evident at 10th, 20th and 30th week respectively. Amarogentin was found to prevent progression of liver carcinogenesis at mild dysplastic stage. Exposure to CCl4/NDEA resulted in upregulation of ppRb807/811, cyclinD1, cdc25A at 10th week and additional activation of cMyc, mdm2 along with downregulation of LimD1, p53, and p21 at 20th week. This was followed by activation of ppRb567 and downregulation of Rbsp3 at 30th week. Prevention of carcinogenesis by amarogentin in both groups might be due to cumulative upregulation of LimD1, Rbsp3, p16 and downregulation of cdc25A at 10th week along with activation of p53, p21 and downregulation of ppRb807/811, ppRb567 at 20th week, followed by downregulation of cyclinD1, cMyc, mdm2 at 30th week. During carcinogenesis reduction of apoptosis was evident since 20th week. However, amarogentin treatment could significantly induce apoptosis through upregulation of the bax-bcl2 ratio, activation of caspase-3 and PARP cleavage. This is the first report of chemopreventive/ therapeutic role of amarogentin during liver carcinogenesis through modulation of cell cycle and apoptosis.
http://carcin.oxfordjournals.org/content/early/2012/09/03/carcin.bgs276.abstract