Jin Rong, Xia Yiqun, Chen Qiuxiang, Li Wulan, Chen Dahui, Ye Hui, Zhao Chengguang, Du Xiaojing, Shi Dengjian, Wu Jianzhang, Liang Guang
Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China; Department of Epidemiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, People's Republic of China.
Drug Des Devel Ther. 2016 Mar 2;10:979-95. doi: 10.2147/DDDT.S90081. eCollection 2016.
The transcription factor nuclear factor-κB (NF-κB) is constitutively activated in a variety of human cancers, including gastric cancer. NF-κB inhibitors that selectively kill cancer cells are urgently needed for cancer treatment. Curcumin is a potent inhibitor of NF-κB activation. Unfortunately, the therapeutic potential of curcumin is limited by its relatively low potency and poor cellular bioavailability. In this study, we presented a novel NF-κB inhibitor named Da0324, a synthetic asymmetric mono-carbonyl analog of curcumin. The purpose of this study is to research the expression of NF-κB in gastric cancer and the antitumor activity and mechanism of Da0324 on human gastric cancer cells.
The expressions between gastric cancer tissues/cells and normal gastric tissues/cells of NF-κB were evaluated by Western blot. The inhibition viability of compounds on human gastric cancer cell lines SGC-7901, BGC-823, MGC-803, and normal gastric mucosa epithelial cell line GES-1 was assessed with the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Absorption spectrum method and high-performance liquid chromatography method detected the stability of the compound in vitro. The compound-induced changes of inducible NF-κB activation in the SGC-7901 and BGC-823 cells were examined by Western blot analysis and immunofluorescence methods. The antitumor activity of compound was performed by clonogenic assay, matrigel invasion assay, flow cytometric analysis, Western blot analysis, and Hoechst 33258 staining assay.
High levels of p65 were found in gastric cancer tissues and cells. Da0324 displayed higher growth inhibition against several types of gastric cancer cell lines and showed relatively low toxicity to GES-1. Moreover, Da0324 was more stable than curcumin in vitro. Western blot analysis and immunofluorescence methods showed that Da0324 blocked NF-κB activation. In addition, Da0324 significantly inhibited tumor proliferation and invasion, arrested the cell cycle, and induced apoptosis in vitro.
The asymmetric mono-carbonyl analog of curcumin Da0324 exhibited significantly improved antigastric cancer activity. Da0324 may be a promising NF-κB inhibitor for the selective targeting of cancer cells. However, further studies are needed in animals to validate these findings for the therapeutic use of Da0324.
转录因子核因子-κB（NF-κB）在包括胃癌在内的多种人类癌症中持续激活。癌症治疗迫切需要能选择性杀死癌细胞的NF-κB抑制剂。姜黄素是NF-κB激活的有效抑制剂。遗憾的是，姜黄素的治疗潜力受到其相对低效和较差的细胞生物利用度的限制。在本研究中，我们提出了一种名为Da0324的新型NF-κB抑制剂，它是姜黄素的合成不对称单羰基类似物。本研究的目的是研究NF-κB在胃癌中的表达以及Da0324对人胃癌细胞的抗肿瘤活性和作用机制。
通过蛋白质免疫印迹法评估胃癌组织/细胞与正常胃组织/细胞中NF-κB的表达差异。用3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴盐法评估化合物对人胃癌细胞系SGC-7901、BGC-823、MGC-803和正常胃黏膜上皮细胞系GES-1的抑制活力。采用吸收光谱法和高效液相色谱法检测化合物在体外的稳定性。通过蛋白质免疫印迹分析和免疫荧光法检测化合物诱导的SGC-7901和BGC-823细胞中诱导型NF-κB激活的变化。通过克隆形成试验、基质胶侵袭试验、流式细胞术分析、蛋白质免疫印迹分析和Hoechst 33258染色试验检测化合物的抗肿瘤活性。
在胃癌组织和细胞中发现高水平的p65。Da0324对几种类型的胃癌细胞系显示出更高的生长抑制作用，对GES-1显示出相对较低的毒性。此外，Da0324在体外比姜黄素更稳定。蛋白质免疫印迹分析和免疫荧光法表明Da0324可阻断NF-κB激活。此外，Da0324在体外显著抑制肿瘤增殖和侵袭，使细胞周期停滞并诱导凋亡。
姜黄素的不对称单羰基类似物Da0324表现出显著改善的抗胃癌活性。Da0324可能是一种有前景的用于选择性靶向癌细胞的NF-κB抑制剂。然而，需要在动物中进行进一步研究以验证这些发现，以便将Da0324用于治疗用途。
