title: Generation of reactive oxygen species by a novel berberine-bile acid analog mediates apoptosis in hepatocarcinoma SMMC-7721 cells.
abstract: 2,3-Methenedioxy-9-O-(3'α,7'α-dihydroxy-5'β-cholan-24'-propy-lester)berberine (B4) is a novel berberine-bile acid analog synthesized in our laboratory. Previously, we showed that B4 exerted greater cytotoxicity than berberine in several human cancer cell lines. Therefore, we further evaluated the mechanism governing its anticancer actions in hepatocellular carcinoma SMMC-7721 cells. B4 inhibited the proliferation of SMMC-7721 cells, and stimulated reactive oxygen species (ROS) production and mitochondrial membrane depolarization; anti-oxidant capacity was reduced. B4 also induced the release of cytochrome c from the mitochondria to the cytosol and an increase in poly ADP-ribose polymerase (PARP) cleavage products, reflective of caspase-3 activation. Moreover, B4 induced the nuclear translocation of apoptosis-inducing factor (AIF) and a rise in DNA fragmentation. Pretreatment with the anti-oxidant N-acetylcysteine (NAC) inhibited B4-mediated effects, including cytotoxicity, ROS production, mitochondrial membrane depolarization increase in intracellular Ca2+, cytochrome c release, PARP cleavage, and AIF translocation. Our data suggest that B4 induces ROS-triggered caspase-dependent and caspase-independent apoptosis pathways in SMMC-7721 cells and that ROS production may be a specific potential strategy for treating hepatic carcinoma.
authors.affiliation: Key Laboratory of Forest Plant Ecology (Northeast Forestry University), Ministry of Education, China. li_qingyong@126.com
authors.forename: Qingyong
authors.initials: Q
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Yuangang
authors.initials: Y
authors.lastname: Zu
authors.forename: Tianyu
authors.initials: T
authors.lastname: Liu
authors.forename: Baoyou
authors.initials: B
authors.lastname: Zhang
authors.forename: Wuna
authors.initials: W
authors.lastname: He
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001599:Berberine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013997:Time Factors
chemical_list: C494829:AIFM1 protein, human; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D001647:Bile Acids and Salts; D017382:Reactive Oxygen Species; D001599:Berberine; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D002118:Calcium; D000111:Acetylcysteine