title: Prevention of liver carcinogenesis by amarogentin through modulation of G1/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.
authors.affiliation: Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road,  Kolkata 700 026, India.
authors.forename: Debolina
authors.initials: D
authors.lastname: Pal
authors.forename: Subhayan
authors.initials: S
authors.lastname: Sur
authors.forename: Suvra
authors.initials: S
authors.lastname: Mandal
authors.forename: Ashes
authors.initials: A
authors.lastname: Das
authors.forename: Anup
authors.initials: A
authors.lastname: Roy
authors.forename: Sukta
authors.initials: S
authors.lastname: Das
authors.forename: Chinmay Kumar
authors.initials: CK
authors.lastname: Panda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation; D018890:Chemoprevention; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D039823:Iridoids / Q000494:pharmacology*; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000187:drug effects*
chemical_list: D039823:Iridoids; D016160:Retinoblastoma Protein; C102609:amarogentin