title: HY253, a novel decahydrofluorene analog, induces apoptosis via intrinsic pathway and cell cycle arrest in liver cancer HepG2 cells.
abstract: Recently, we isolated HY253, a novel decahydrofluorene analog with a molecular structure of 7,8a-divinyl-2,4a,4b,5,6,7,8,8a,9,9a-decahydro-1H-fluorene-2,4a,4b,9a-tetraol from the roots of Aralia continentalis, which is known as Dokwhal, a traditional medicinal herb. Moreover, we previously reported its cytotoxic activity on cancer cell proliferation in human lung cancer A549 and cervical cancer HeLa cells. The current study aimed to evaluate its detailed molecular mechanisms in cell cycle arrest and apoptotic induction in human hepatocellular carcinoma HepG2 cells. Flow cytometric analysis of HepG2 cells treated with 60 micrometer HY253 revealed appreciable cell cycle arrest at the G1 phase via inhibition of Rb phosphorylation and down-regulation of cyclin D1. Furthermore, using western blots, we found that up-regulation of cyclin-dependent kinase inhibitors, such as p21(CIP1) and p27(KIP1), was associated with this G1 phase arrest. Moreover, TUNEL assay and immunoblottings revealed apoptotic induction in HepG2 cells treated with 100 micrometer HY253 for 24 h, which is associated with cytochrome c release from mitochondria, via down-regulation of anti-apoptotic Bcl-2 protein, which in turn resulted in activation of caspase-9 and -3, and proteolytic cleavage of poly(ADP-ribose) polymerase (PARP). Accordingly, we suggest that HY253 may be a potent chemotherapeutic hit compound for treating human liver cancer cells via up-regulation and activation of the p53 gene.
authors: Department of Pharmacy, College of Pharmacy, Hanyang University, Kyeonggido 426-791, Republic of Korea.
authors: Ko-woon
authors: KW
authors: Choi
authors: Hyewon
authors: H
authors: Suh
authors: Seunghun
authors: S
authors: Jang
authors: Dongsik
authors: D
authors: Kim
authors: Chul-Hoon
authors: CH
authors: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D027983:Aralia / Q000737:chemistry; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000494:pharmacology; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D005434:Flow Cytometry; D005449:Fluorenes / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D008928:Mitochondria / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C539892:7,8a-divinyl-2,4a,4b,5,6,7,8,8a,9,9a-decahydro-1H-fluorene-2,4a,4b,9a-tetraol; C000595707:BCL2 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005449:Fluorenes; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D018844:Cyclin-Dependent Kinases; D053148:Caspase 3; D053453:Caspase 9