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

作者：Kim Seo Ju; Park Hyun Ki; Kim Ju Young; Yoon Jin Sun; Kim Eun Shil; Cho Cheon Gyu; Kim Byoung Kook; Park Byeong Bae; Lee Young Yiul^*

来源：Acta Pathologica, Microbiologica et Immunologica Scandinavica, 2012, 120(10): 836-845.

DOI：10.1111/j.1600-0463.2012.02916.x

• HYU-01
• (+/-) trans-dihydronarciclasine
• cell cycle
• apoptosis
• p27
• acute myeloid leukemia

(+/-) 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.

• 出版日期2012-10