(–)-Syringaresinol inhibits proliferation of human promyelocytic HL-60 leukemia cells via G1 arrest and apoptosis

• Published in: International immunopharmacology 2008-07, Vol.8 (7), p.967-973
• Main Authors: Park, Bo-Young, Oh, Sei-Ryang, Ahn, Kyung-Seop, Kwon, Ok-Kyong, Lee, Hyeong-Kyu
• Format: Article
• Language: English
• Subjects: (−)-syringaresinol; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Bax; Bcl-2; Biological and medical sciences; Caspase-3; Cdk; Cdki; Cell Proliferation - drug effects; Cytochromes c - secretion; Daphne; Furans - pharmacology; G1 Phase - drug effects; Hematologic and hematopoietic diseases; HL-60 Cells; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lignans - pharmacology; Medical sciences; Pharmacology. Drug treatments; Poly(ADP-ribose) Polymerases - metabolism; Proto-Oncogene Proteins c-bcl-2 - analysis
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2008.02.012

We examined the effect of (−)-syringaresinol, a furofuran-type lignan isolated from Daphne genkwa, on cell cycle regulation in HL-60 human promyelocytic leukemia cells in vitro. (−)-Syringaresinol decreased the viability of HL-60 cells by inducing G 1 arrest followed by apoptosis in a dose- and time-dependent manner. The G 0/G 1 phase of the cell cycle is regulated by cyclin-dependent kinases (Cdk), cyclins and cyclin-dependent kinase inhibitors (Cdki). We show by western blot analysis, that the (−)-syringaresinol-induced G 1 arrest was mediated through the increased expression of Cdki proteins (p21 cip1/waf1 and p27 kip1) with a simultaneous decrease in cdk2, cdk4, cdk6, cyclin D 1, cyclin D 2, and cyclin E expression. The induction of apoptosis after treatment with (−)-syringaresinol for 24 h was demonstrated by morphological changes, DNA fragmentation, altered ratio of Bax/Bcl-2, cleavage of poly(ADP-ribose) polymerase and flow cytometry analysis. (−)-Syringaresinol also induced cytochrome c release and activation of caspase-3 and caspase-9. To our knowledge, this is the first time that (−)-syringaresinol has been reported to potently inhibit the proliferation of human promyelocytic HL-60 cells through G 1 arrest and induction of apoptosis. These findings suggest that (−)-syringaresinol may be a potential chemotherapeutic agent for the treatment of cancer.