A Novel Monocarbonyl Analogue of Curcumin, (1E,4E)-1,5-Bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one, Induced Cancer Cell H460 Apoptosis via Activation of Endoplasmic Reticulum Stress Signaling Pathway
A Novel Monocarbonyl Analogue of Curcumin, (1E,4E)-1,5-Bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one, Induced Cancer Cell H460 Apoptosis via Activation of Endoplasmic Reticulum Stress Signaling Pathway
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姜黄素的新型单羰基类似物 (1E,4E)-1,5-双(2,3-二甲氧基苯基)penta-1,4-dien-3-one 通过激活内质网应激信号通路诱导癌细胞 H460 凋亡
DOI：
10.1021/jm200017g
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发表时间：
2011-06-09
影响因子：
7.3
通讯作者：
Liang, Guang
中科院分区：
文献类型：
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作者：
Wang, Yi;Xiao, Jian;Liang, Guang
内质网应激诱导的肿瘤细胞凋亡已成为肿瘤治疗药物开发的新的信号转导靶点。姜黄素对多种癌细胞表现出生长抑制活性。我们以前合成了一系列姜黄素的单羰基类似物，对肿瘤细胞具有很强的细胞毒性。在本研究中，我们发现只有化合物19 [（1 E，4 E）-1，5-双（2，3-二甲氧基苯基）戊-1，4-二烯-3-酮]可以诱导人肺癌H460细胞表达C/EBP同源蛋白（CHOP）。19以剂量反应性方式诱导H460细胞凋亡，这种作用与ER应激介导的凋亡途径中一系列关键组分的相应增加，随后是caspase裂解和激活有关。然而，相同浓度的姜黄素不显示这些特性。通过特异性siRNA敲低CHOP减弱了19诱导的细胞凋亡，进一步表明凋亡途径是ER应激依赖性的。在体内，19在治疗22天后显示H460异种移植肿瘤大小显著减少53.5%。总之，这些对新型化合物19的机制见解，具有无毒性，可能为我们提供一种新的抗癌候选药物。
Endoplasmic reticulum (ER) stress-induced cancer cell apoptosis has become a novel signaling target for development of cancer therapeutic drugs. Curcumin exhibits growth-suppressive activity against a variety of cancer cells. We previously synthesized a series of monocarbonyl analogues of curcumin with strong cytotoxicity against tumor cells. In this study, we found that only compound 19 [(1E,4E)-1,5-bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one] can induce C/EBP-homologous protein (CHOP) expression in human lung cancer H460 cells. Treatment with 19 induced H460 cell apoptosis in a dose-responsive manner, and this effect was associated with corresponding increases in a series of key components in ER stress-mediated apoptosis pathway, followed by caspase cleavage and activation. However, curcumin at the same concentrations does not display such properties. CHOP knockdown by specific siRNA attenuated 19-induced cell apoptosis, further indicating that the apoptotic pathway is ER stress-dependent. In vivo, 19 showed a dramatic 53.5% reduction in H460 xenograft tumor size after 22 days of treatment. Taken together, these mechanistic insights on the novel compound 19, with nontoxicity, may provide us with a novel anticancer candidate.