Caspase-8 preferentially senses the apoptosis-inducing action of NG-18, A gambogic acid derivative, in human leukemia HL-60 cells
Caspase-8 preferentially senses the apoptosis-inducing action of NG-18, A gambogic acid derivative, in human leukemia HL-60 cells
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DOI：
10.4161/cbt.6.5.3960
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发表时间：
2007-05
影响因子：
3.6
通讯作者：
Zhijian Tao;Yunlong Zhou;Jin-jian Lu;W. Duan;Xinxia He;Li-ping Lin;Jian Ding;Yu-xin Qin
中科院分区：
文献类型：
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作者：
Zhijian Tao;Yunlong Zhou;Jin-jian Lu;W. Duan;Xinxia He;Li-ping Lin;Jian Ding;Yu-xin Qin
藤黄酸（Gambogic acid，GA）是中药藤黄（Garcinia hanburryi）中藤黄的主要活性成分，具有较强的抗肿瘤活性。GA的衍生物N-（2-乙氧基乙基）藤黄酰胺（NG-18）也有效地抑制培养的人肿瘤细胞的增殖。NG-18的抑制作用与其诱导细胞凋亡的能力有关。NG-18可明显诱导HL-60细胞凋亡，且外源性和内源性凋亡途径几乎同时被激活。NG-18诱导的肿瘤细胞凋亡与促凋亡Bcl-2家族成员Bax的上调和抗凋亡蛋白Bcl-2的下调有关。泛半胱天冬酶抑制剂Z-VAD-FMK可完全阻断NG-18诱导的细胞凋亡，表明半胱天冬酶在此过程中起着积极的作用。用Z-IETD-FMK特异性抑制caspase-8活性可显著阻断NG-18诱导的细胞凋亡。相反，分别使用Z-VDVAD-FMK或Z-LEHD-FMK抑制其它引发剂caspase-2或-9对NG-18诱导的细胞凋亡没有影响。总之，我们的数据表明，NG-18诱导的细胞凋亡依赖于caspase-8，caspase-8在这一事件中起着关键的执行者作用。
Gambogic acid (GA) is the major active ingredient of gamboge secreted from a Chinese traditional medicine Garcinia hanburryi possessing potent anti-tumor activity. N-(2-ethoxyethyl)gambogamide (NG-18), a derivative of GA, also efficiently inhibits proliferation of cultured human tumor cells. The inhibition effect of NG-18 is associated with its ability to induce apoptosis. In the present study, NG-18 markedly induced leukemia HL-60 cells apoptosis, and the extrinsic and intrinsic apoptosis pathways were activated almost at the same time. NG-18-induced tumor cell apoptosis was associated with up-regulation of pro-apoptotic Bcl-2 family member Bax, and down-regulation of anti-apoptotic protein Bcl-2. The NG-18-induced apoptosis was blocked completely by a pan-caspase inhibitor Z-VAD-FMK, indicating that caspases were functionally and actively involved in this process. The specific inhibition of caspase-8 activity using Z-IETD-FMK significantly blocked NG-18-induced apoptosis. In contrast, inhibition of other initiator caspases, caspase-2 or -9, using Z-VDVAD-FMK or Z-LEHD-FMK respectively had no effect on NG-18-induced apoptosis. Altogether, our data demonstrated that NG-18-induced apoptosis was dependent on caspases and caspase-8 acted as a key executor in the event.