Prevention of liver carcinogenesis by amarogentin through modulation of G 1 /S cell cycle check point and induction of apoptosis

Abstract

Amarogentin, a secoiridoid glycoside, is an active component of the medicinal plant Swertia chirata. In this study, chemopreventive and chemotherapeutic actions of amarogentin were evaluated in a carbon tetrachloride (CCl(4))/N-nitrosodiethylamine (NDEA)-induced liver carcinogenesis mouse model system during continuous and posttreatment 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 were evident at 10th, 20th and 30th week, respectively. Amarogentin was found to prevent progression of liver carcinogenesis at mild dysplastic stage. Exposure to CCl(4)/NDEA resulted in upregulation of ppRb807/811, cyclinD1 and cdc25A at 10th week and additional activation of cMyc and 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 and p21 and downregulation of ppRb807/811 and ppRb567 at 20th week, followed by downregulation of cyclinD1, cMyc and 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 poly ADP ribose polymerase cleavage. This is the first report of chemopreventive/therapeutic role of amarogentin during liver carcinogenesis through modulation of cell cycle and apoptosis.

Reduction of Proliferation and Induction of Apoptosis are Associated with Shrinkage of Head and Neck Squamous Cell Carcinoma due to Neoadjuvant Chemotherapy

“…Similar data has not yet been reported. However, increase in RBSP3 and LIMD1 expression, along with down-regulation of pRB expression has been reported in chemoprevention of liver carcinogenesis in mouse by amarogentin (Pal et al, 2012). On the other hand, reduced expression of cMYC in some post-therapy tumors (5/11) indicates the importance of this gene in inhibition of cell proliferation.…”

Transcriptional and Translational Regulation of C/EBPβ-HDAC1 Protein Complexes Controls Different Levels of p53, SIRT1, and PGC1α Proteins at the Early and Late Stages of Liver Cancer

“…We focused our studies on three main targets of the C/EBP␤-HDAC1 complexes: p53, SIRT1, and PGC1␣, and on consequences of the down-regulation of p53 at late stages of liver cancer. It has been shown that the p53-p21 pathway inhibits liver proliferation and that it is eliminated during development of liver cancer (23,24). However, the mechanism of this elimination has not been shown.…”

Amarogentin Induces Apoptosis of Liver Cancer Cells via Upregulation of p53 and Downregulation of Human Telomerase Reverse Transcriptase in Mice

“…15 Additionally, a dose of 0.2 mg/g has been reported to elicit a good response in HCC mice. 8,9 Thus, a 0.2 mg/g/d dose was selected for the animal experiments. A 5 Â 10 6 (0.2 mL) aliquot of HepG2 cells was injected subcutaneously into the left flank of each mouse.…”