School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
PLoS One. 2011 Jan 25;6(1):e15843. doi: 10.1371/journal.pone.0015843.
β-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 β-elemene, 13-(3-methyl-1-piperazinyl)-β-elemene (DX1), 13-(cis-3,5-dimethyl-1-piperazinyl)-β-elemene (DX2), 13-(4-ethyl-1-piperazinyl)-β-elemene (DX3), 13-(4-isopropyl-1-piperazinyl)-β-elemene (DX4) and 13-piperazinyl-β-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(2)O(2)), a decrease of mitochondrial membrane potential (MMP), and the activation of caspase-8. Pretreatment with the antioxidants N-acetylcysteine and catalase completely blocked DX1-induced H(2)O(2) production, but only partially its activation of caspase-8 and induction of apoptosis. HL-60 cells were more sensitive than its H(2)O(2)-resistant subclone HP100-1 cells to DX1-induced apoptosis. The activation of caspase-8 by these compounds was correlated with the decrease in the levels of cellular FLICE-inhibitory protein (c-FLIP). The proteasome inhibitor MG-132 augmented the decrease in c-FLIP levels and apoptosis induced by these derivatives. FADD- and caspase-8-deficient Jurkat subclones have a decreased response to DX1-induced apoptosis. Our data indicate that these novel β-elemene piperazine derivatives induce apoptosis through the decrease in c-FLIP levels and the production of H(2)O(2) which leads to activation of both death receptor- and mitochondrial-mediated apoptotic pathways.
β-榄香烯是莪术的一种有效成分，具有抗肿瘤活性。为了提高其抗肿瘤活性，我们合成了 5 种新型的β-榄香烯哌嗪衍生物，分别为 13-(3-甲基-1-哌嗪基)-β-榄香烯(DX1)、13-(顺式-3,5-二甲基-1-哌嗪基)-β-榄香烯(DX2)、13-(4-乙基-1-哌嗪基)-β-榄香烯(DX3)、13-(4-异丙基-1-哌嗪基)-β-榄香烯(DX4)和 13-哌嗪基-β-榄香烯(DX5)。这些衍生物在人白血病 HL-60、NB4、K562 和 HP100-1 细胞中的增殖抑制和凋亡诱导作用被检测。含有仲氨基的 DX1、DX2 和 DX5 比 DX3 和 DX4 更能有效地抑制细胞生长和诱导凋亡。DX1 的诱导凋亡能力与过氧化氢(H2O2)的产生、线粒体膜电位(MMP)的降低以及半胱天冬酶-8 的激活有关。抗氧化剂 N-乙酰半胱氨酸和过氧化氢酶预处理完全阻断了 DX1 诱导的 H2O2 产生，但仅部分阻断了半胱天冬酶-8 的激活和凋亡的诱导。HL-60 细胞比其 H2O2 耐药亚克隆 HP100-1 细胞对 DX1 诱导的凋亡更为敏感。这些化合物对半胱天冬酶-8 的激活与细胞 FLICE 抑制蛋白(c-FLIP)水平的降低有关。蛋白酶体抑制剂 MG-132 增强了这些衍生物诱导的 c-FLIP 水平降低和凋亡。FADD-和半胱天冬酶-8 缺陷型 Jurkat 亚克隆对 DX1 诱导的凋亡反应降低。我们的数据表明，这些新型的β-榄香烯哌嗪衍生物通过降低 c-FLIP 水平和产生 H2O2 诱导凋亡，导致死亡受体和线粒体介导的凋亡途径的激活。
