Da0324, an inhibitor of nuclear factor-κB activation, demonstrates selective antitumor activity on human gastric cancer cells.
Da0324, an inhibitor of nuclear factor-κB activation, demonstrates selective antitumor activity on human gastric cancer cells.
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DOI：
10.2147/dddt.s90081
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Liang G
中科院分区：
文献类型：
--
作者：
Jin R;Xia Y;Chen Q;Li W;Chen D;Ye H;Zhao C;Du X;Shi D;Wu J;Liang G
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被组成性激活。选择性杀死癌细胞的NF-κB抑制剂是癌症治疗的迫切需要。姜黄素是NF-κB活化的有效抑制剂。不幸的是，姜黄素的治疗潜力受到其相对较低的效力和较差的细胞生物利用度的限制。在本研究中，我们提出了一种新的NF-κB抑制剂Da 0324，一种合成的姜黄素的不对称单羰基类似物。本研究旨在探讨NF-κB B在胃癌中的表达及Da 0324对胃癌细胞的抑制作用及其机制。Western blot检测胃癌组织/细胞和正常胃组织/细胞NF-κB的表达。化合物对人胃癌细胞系SGC-7901、BGC-823、MGC-803和正常胃粘膜上皮细胞系GES-1的抑制活力用3-[4，5-二甲基噻唑-2-基]-2，5-二苯基四唑溴化物测定法评估。采用紫外吸收光谱法和高效液相色谱法考察了该化合物的体外稳定性。Western blot和免疫荧光法检测化合物对SGC-7901和BGC-823细胞诱导型NF-κB活化的影响。化合物的抗肿瘤活性通过克隆形成测定、基质胶侵袭测定、流式细胞术分析、Western印迹分析和Hoechst 33258染色测定来进行。p65在胃癌组织和细胞中呈高水平表达。Da 0324对几种胃癌细胞株显示出较高的生长抑制作用，对GES-1显示出相对较低的毒性。此外，Da 0324在体外比姜黄素更稳定。Western blot分析和免疫荧光检测结果表明，Da 0324可阻断NF-κB的活化。此外，Da 0324在体外可显著抑制肿瘤的增殖和侵袭，阻滞细胞周期，诱导细胞凋亡。姜黄素Da 0324的不对称单羰基类似物具有显著提高的抗胃癌活性。Da 0324可能是一种有希望的选择性靶向肿瘤细胞的NF-κB抑制剂。然而，需要在动物中进行进一步的研究，以验证Da 0324治疗用途的这些发现。
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.