title: Rhein triggers apoptosis via induction of endoplasmic reticulum stress, caspase-4 and intracellular calcium in primary human hepatic HL-7702 cells.
abstract: Rhein is an active component of rhubarb; a traditional Chinese medicine reported to induce apoptosis and cause liver toxicity. However, rhein's apoptotic-inducing effects, as well as its molecular mechanisms of action on hepatic cells need to be further explored. In the present study, rhein was found to trigger apoptosis in primary human hepatic HL-7702 cells as showed by annexin V/PI double staining assay and nuclear morphological changes demonstrated by Hoechst 33258 staining. Moreover, it was observed that the mechanism implicated in rhein-induced apoptosis was caspase-dependent, presumably via ER-stress associated pathways, as illustrated by up-regulation of glucose-regulated protein 78 (GRP 78), PKR-like ER kinase (PERK), C-Jun N-terminal kinase (JNK) and CCAAT/enhancer-binding protein homologous protein (CHOP). Meanwhile, caspase-4 as a hallmark of ER-stress, was also showed to be activated following by caspase-3 activation. Furthermore, rhein also promoted intracellular elevation of calcium that contributed in apoptosis induction. Interestingly, pre-treatment with calpain inhibitor I reduced the effects of rhein on apoptosis induction and JNK activation. These data suggested that rhein-induced apoptosis through ER-stress and elevated intracellular calcium level in HL-7702 cells.
authors.affiliation: Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Arouna
authors.initials: A
authors.lastname: KoraMagazi
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Bashir
authors.initials: B
authors.lastname: Yousef
authors.affiliation: Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Mounia
authors.initials: M
authors.lastname: Guerram
authors.affiliation: Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China; Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing, Jiangsu, China. Electronic address: yufengcpu14@yahoo.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Yu
mesh_terms: D000880:Anthraquinones / Q000737:chemistry*; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053471:Caspases, Initiator / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000473:pathology*; D008856:Microscopy, Fluorescence
chemical_list: D000880:Anthraquinones; D004791:Enzyme Inhibitors; D007770:L-Lactate Dehydrogenase; C505407:CASP3 protein, human; C093516:CASP4 protein, human; D053148:Caspase 3; D053471:Caspases, Initiator; D002118:Calcium; C020491:rhein
keywords: Apoptosis; Calcium; Caspase-4; HL-7702 cells; Rhein