Anti-leukemic effect of a synthetic compound, (+/-) trans-dihydronarciclasine (HYU-01) via cell-cycle arrest and apoptosis in acute myeloid leukemia

Abstract

(±) trans?Dihydronarciclasine, isolated from Chinese medicinal plant Zephyranthes candida, has been shown to possess quite potent anti?tumoral effect against selected human cancer cell lines. However, little is known about the anti?tumoral effect of (±) trans?dihydronarciclasine in acute myeloid leukemia (AML). This study was performed to investigate the effect of a novel synthetic (±) trans?dihydronarciclasine (code name; HYU?01) in AML. The HYU?01 inhibited the proliferation of various AML cell lines including HL?60 as well as primary leukemic blasts in a dose?dependent manner. To investigate the mechanism of the anti?proliferative effect of HYU?01, cell?cycle analysis was attempted in HL?60 cells, resulting in G1 arrest. The expression levels of CDK2, CDK4, CDK6, cyclin E, and cyclin A were decreased in a time?dependent manner. In addition, HYU?01 up?regulated the expression of the p27, and markedly enhanced the binding of p27 with CDK2, 4, and 6, ultimately resulting in the decrease of their kinase activities. Furthermore, HYU?01 induced the apoptosis through the induction of proapoptotic molecules and reduction of antiapoptotic molecules in association with the activation of caspase?3, ?8, and ?9. These results suggest that HYU?01 may inhibit the proliferation of HL?60 cells, via apoptosis, as well as G1 block in association with the induction of p27.