RRC ID 52420
Author Okubo S, Uto T, Goto A, Tanaka H, Nishioku T, Yamada K, Shoyama Y.
Title Berberine Induces Apoptotic Cell Death via Activation of Caspase-3 and -8 in HL-60 Human Leukemia Cells: Nuclear Localization and Structure-Activity Relationships.
Journal Am J Chin Med
Abstract Berberine (BBR), an isoquinoline alkaloid, is a well-known bioactive compound contained in medicinal plants used in traditional and folk medicines. In this study, we investigated the subcellular localization and the apoptotic mechanisms of BBR were elucidated. First, we confirmed the incorporation of BBR into the cell visually. BBR showed antiproliferative activity and promptly localized to the nucleus from 5[Formula: see text]min to 15[Formula: see text]min after BBR treatment in HL-60 human promyelocytic leukemia cells. Next, we examined the antiproliferative activity of BBR (1) and its biosynthetically related compounds (2-7) in HL-60 cells. BBR exerted strongest antiproliferative activity among 1-7 and the results of structures and activity relation suggested that a methylenedioxyl group in ring A, an [Formula: see text]-alkyl group at C-9 position, and the frame of isoquinoline may be necessary for antiproliferative activity. Moreover, BBR showed the most potent antiproliferative activity in HL-60 cells among human cancer and normal cell lines tested. Next, we examined the effect of BBR on molecular events known as apoptosis induction. In HL-60 cells, BBR induced chromatin condensation and DNA fragmentation, and triggered the activation of PARP, caspase-3 and caspase-8 without the activation of caspase-9. BBR-induced DNA fragmentation was abolished by pretreatment with inhibitors against caspase-3 and caspase-8, but not against caspase-9. ERK and p38 were promptly phosphorylated after 15 min of BBR treatment, and this was correlated with time of localization to the nucleus of BBR. These results demonstrated that BBR translocated into nucleus immediately after treatments and induced apoptotic cell death by activation of caspase-3 and caspase-8.
Volume 45(7)
Pages 1497-1511
Published 2017-1-1
DOI 10.1142/S0192415X17500811
PMID 29025293
MeSH Apoptosis / drug effects* Berberine / metabolism* Berberine / pharmacology* Caspase 3 / metabolism* Caspase 8 / metabolism* Cell Nucleus / metabolism* Cell Proliferation / drug effects Cells, Cultured Chromatin / metabolism DNA Fragmentation / drug effects Extracellular Signal-Regulated MAP Kinases / metabolism HL-60 Cells Humans Leukemia, Promyelocytic, Acute / metabolism Leukemia, Promyelocytic, Acute / pathology* Phosphorylation / drug effects Structure-Activity Relationship p38 Mitogen-Activated Protein Kinases / metabolism
IF 3.682
Times Cited 21
Human and Animal Cells Kato III(RCB2088) Hep G2(RCB1886) CACO-2(RCB0988)