title: 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.
authors.affiliation: Laboratory of Hematopoiesis and Hematologic Malignancy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Seo Ju
authors.initials: SJ
authors.lastname: Kim
authors.forename: Hyun Ki
authors.initials: HK
authors.lastname: Park
authors.forename: Ju Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Jin Sun
authors.initials: JS
authors.lastname: Yoon
authors.forename: Eun Shil
authors.initials: ES
authors.lastname: Kim
authors.forename: Cheon-Gyu
authors.initials: CG
authors.lastname: Cho
authors.forename: Byoung Kook
authors.initials: BK
authors.lastname: Kim
authors.forename: Byeong Bae
authors.initials: BB
authors.lastname: Park
authors.forename: Young Yiul
authors.initials: YY
authors.lastname: Lee
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D016213:Cyclins; D018809:Proliferating Cell Nuclear Antigen; C413374:p27 antigen; C064338:dihydronarciclasine; D018844:Cyclin-Dependent Kinases; D020169:Caspases