β-elemene piperazine derivatives induce apoptosis in human leukemia cells through downregulation of c-flip and generation of rosβ-elemene哌嗪衍生物诱导细胞凋亡在人类白血病细胞的差别通过对这些c-flip和ros的生成.pdf

b-Elemene Piperazine Derivatives Induce Apoptosis in Human Leukemia Cells through Downregulation of c-FLIP and Generation of ROS 1¤ 3 2 2 2 3 Zhiying Yu , Rui Wang , Liying Xu , Siwei Xie , Jinhua Dong , Yongkui Jing * 1 School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China, 2 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China, 3 Department of Medicine, The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York, United States of America Abstract b-Elemene is an active component of the herb medicine Curcuma Wenyujin with reported antitumor activity. To improve its antitumor ability, five novel piperazine derivatives of b-elemene, 13-(3-methyl-1-piperazinyl)-b-elemene (DX1), 13-(cis-3,5- dimethyl-1-piperazinyl)-b-elemene (DX2), 13-(4-ethyl-1-piperazinyl)-b-elemene (DX3), 13-(4-isopropyl-1-piperazinyl)-b-ele- mene (DX4) and 13-piperazinyl-b-elemene (DX5), were synthesized. The antiproliferative and apoptotic effects of these derivatives were determined in human leukemia HL-60, NB4, K562 and HP100-1 cells. DX1, DX2 and DX5, which contain a secondary amino moiety, were more active in inhibiting cell growth and in inducing apoptosis than DX3 and DX4. The apoptosis induction ability of DX1 was associated with the generation of hydrogen peroxide (H O ), a decrease of 2 2 mitochondrial membrane potential (MMP), and the activation of caspase-8. Pretreatment with the antioxidants