4-Hydroxyderricin from Angelica keiskei roots induces caspase-dependent apoptotic cell death in HL60 human leukemia cells.
The ethyl acetate (EtOAc)-soluble fraction of a methanol extract of Angelica keiskei roots exhibited cytotoxic activity against 4 human tumor cell lines, HL60 (leukemia), CRL1579 (melanoma), A549 (lung), and AZ521 (stomach). Nine chalcones (1-9), 5 coumarins (10-14), and 4 flavanones (15-18), isolated from the EtOAc-soluble fraction, were examined for their cytotoxic activities in the 4 human tumor cell lines. Among the compounds tested, 4-hydroxyderricin (2), a major chalcone constituent, exhibited potent cytotoxic activities in all 4 tumor cell lines with IC(50) values of 5.5 µM (HL60), 4.8 µM (CRL1579), 10.2 µM (A549), and 4.2 µM (AZ521). 4-Hydroxyderricin induced early apoptosis in HL60 cells, observed as membrane phospholipid exposure in flow cytometry. Western blot analysis showed that 4-hydroxyderricin markedly reduced the levels of procaspases-3, -8, and -9, while increasing the levels of cleaved caspases-3, -8, and -9. In addition, 4-hydroxyderricin exhibited potent inhibitory activity on human DNA topoisomerase (Topo) II (IC(50) 21.9 µM). These results suggested that 4-hydroxyderricin induces apoptotic cell death in HL60 via both the death receptor-mediated pathway and the mitochondrial pathway by, at least in part, Topo II inhibition. 4-Hydroxyderricin may therefore hold promise as an effective antitumor agent.
College of Science and Technology, Nihon University, Tokyo, Japan. akihisa@chem.cst.nihon-u.ac.jp
Toshihiro
T
Akihisa
Takashi
T
Kikuchi
Hisashi
H
Nagai
Koichi
K
Ishii
Keiichi
K
Tabata
Takashi
T
Suzuki
D029969:Angelica / Q000737:chemistry*; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism*; D002599:Chalcone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D008517:Phytotherapy; D018517:Plant Roots / Q000737:chemistry*; D011419:Propidium / Q000378:metabolism; D059003:Topoisomerase Inhibitors / Q000494:pharmacology
D017304:Annexin A5; D059003:Topoisomerase Inhibitors; D011419:Propidium; C068243:4-hydroxyderricin; D002599:Chalcone; D020169:Caspases; D004250:DNA Topoisomerases, Type II