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

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 G1 arrest followed by apoptosis in a dose- and time-dependent manner. The G0/G1 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 G1 arrest was mediated through the increased expression of Cdki proteins (p21cip1/waf1 and p27kip1) with a simultaneous decrease in cdk2, cdk4, cdk6, cyclin D1, cyclin D2, 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 G1 arrest and induction of apoptosis. These findings suggest that (−)-syringaresinol may be a potential chemotherapeutic agent for the treatment of cancer.