Da0324, an inhibitor of nuclear factor-κB activation, demonstrates selective antitumor activity on human gastric cancer cells
Received 8 June 2015
Accepted for publication 23 October 2015
Published 2 March 2016 Volume 2016:10 Pages 979—995
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 4
Editor who approved publication: Prof. Dr. Wei Duan
Rong Jin,1,3,* Yiqun Xia,1,2,* Qiuxiang Chen,1,2 Wulan Li,2,4 Dahui Chen,2 Hui Ye,2,5 Chengguang Zhao,2 Xiaojing Du,1,2 Dengjian Shi,2 Jianzhang Wu,2 Guang Liang2
1Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, 2Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, 3Department of Epidemiology, The First Affiliated Hospital of Wenzhou Medical University, 4College of Information Science and Computer Engineering, Wenzhou Medical College, 5School of Basic Medical Sciences, Wenzhou Medical College, Wenzhou, People’s Republic of China
*These authors contributed equally to this work
Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
Keywords: gastric cancer, anticancer drug, NF-κB inhibitor, asymmetric MACs, apoptosis, curcumin