A synthetic compound, 1,5‐bis(2‐methoxyphenyl)penta‐ 1,4‐dien‐3‐one (B63), induces apoptosis and activates endoplasmic reticulum stress in non‐small cell lung cancer cells
A synthetic compound, 1,5‐bis(2‐methoxyphenyl)penta‐ 1,4‐dien‐3‐one (B63), induces apoptosis and activates endoplasmic reticulum stress in non‐small cell lung cancer cells
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DOI：
10.1002/ijc.27406
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发表时间：
2012-09
影响因子：
6.4
通讯作者：
Jian Xiao;Yi Wang;Jing Peng;Lu Guo;Jie Hu;M. Cao;Xie Zhang;Hangyu Zhang;Zhouguang Wang
中科院分区：
文献类型：
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作者：
Jian Xiao;Yi Wang;Jing Peng;Lu Guo;Jie Hu;M. Cao;Xie Zhang;Hangyu Zhang;Zhouguang Wang
内质网（ER）应激诱导的癌细胞凋亡已成为开发癌症治疗药物的新型信号转导靶点。姜黄素是一种膳食植物化学物质，通过多靶点机制对癌细胞表现出生长抑制活性。但其稳定性差、药代动力学不佳等问题严重限制了其临床应用。因此，我们设计并合成了一种新的姜黄素单羰基类似物，1，5-双（2-甲氧基苯基）戊-1，4-二烯-3-酮（B63）。该化合物在培养基中表现出更高的化学稳定性和比姜黄素更好的细胞内分布。B63处理以剂量响应方式有效诱导人非小细胞肺癌（NSCLC）细胞凋亡，而在正常肺成纤维细胞中无细胞毒性。其抗肿瘤作用与ER应激介导的凋亡途径相关，最终与caspase级联的激活相关。但相同浓度的姜黄素对H460细胞的内质网应激无明显影响。此外，通过siRNA敲低C/EBP同源蛋白减弱了B63诱导的细胞凋亡，表明凋亡途径是ER应激依赖性的。体内实验中，B63预处理H460肿瘤细胞后，移植瘤体积和重量明显减小。总之，从化学和生物学角度对新型化合物B63的这些见解可能为治疗NSCLC提供新的抗癌候选药物。
Endoplasmic reticulum (ER) stress‐induced cancer cell apoptosis has become a novel signaling target for the development of therapeutic drugs for cancer treatment. Curcumin, a dietary phytochemical, exhibits growth‐suppressive activity against cancer cells via multitarget mechanisms. However, the low stability and poor pharmacokinetics significantly limit its clinical applications. Thus, we designed and synthesized a novel monocarbonyl analog of curcumin, 1,5‐bis(2‐methoxyphenyl) penta‐1,4‐dien‐3‐one (B63). This compound exhibited a higher chemical stability in cultural medium and a better intracellular profile than curcumin. Treatment with B63 potently induced apoptosis of human non‐small cell lung cancer (NSCLC) cells in a dose‐responsive manner, while exhibiting no cytotoxicity in normal lung fibroblast cells. Its antitumor effect was associated with the ER stress‐mediated apoptotic pathway and, ultimately, the activation of the caspase cascades. However, curcumin at the same concentrations did not cause ER stress in H460 cells. Further, C/EBP homologous protein knockdown by siRNA attenuated B63‐induced cell apoptosis, indicating that the apoptotic pathway is ER stress‐dependent. In vivo, the volume and weight of the tumor were reduced significantly by pretreating the H460 tumor cells with B63 before implantation. Taken together, these insights on the novel compound B63, from both chemical and biological perspectives, may provide a novel anticancer candidate for the treatment of NSCLC.