新型环四肽HDAC抑制剂的化学合成及其对乳腺癌细胞增殖和迁移的抑制作用

目的:化学合成新型环四肽组蛋白去乙酰化酶（histone deacetylase，HDAC）抑制剂并探索其对抗乳腺癌的作用及机制。方法:基于天然环四肽chlamydocin的化学结构特征优化设计新型环四肽HDAC抑制剂。应用CCK8、Hoechst染色、流式细胞仪以及划痕实验等方法评价该抑制剂的抗乳腺癌活性。Western blot方法被用于初步探索该抑制剂的可能作用机制。结果:质谱结果显示我们成功合成了新型环四肽HDAC抑制剂。细胞学检测发现，该抑制剂可显著抑制乳腺癌细胞系T47D和MCF7的细胞增殖和细胞迁移。环四肽HDAC抑制剂对MCF7和T47D的IC50分别为3.0 nmol/L和2.5 nmol/L。细胞凋亡检测结果提示HDAC抑制剂处理细胞后，细胞凋亡水平显著增强。此外，经过该抑制剂处理之后，APOE蛋白表达水平显著上调，而SREBP2和HMGCR蛋白表达水平显著下调，提示环四肽HDAC抑制剂在脂代谢方面的潜在作用。结论:新型合成的环四肽HDAC抑制剂可有效抑制乳腺癌细胞增殖和迁移，或有望为乳腺癌治疗提供新的治疗药物。

Inhibitory effect of a novel synthetic cyclic tetra-peptide HDAC inhibitor on proliferation and migration of breast cancer cells

Objective:To explore the anticancer efficacy and mechanism of synthetic cyclic tetra-peptide histone deacetylase (HDAC) inhibitor in breast cancer.Methods:A novel cyclic tetra-peptide HDAC inhibitor was designed and synthesized based on the framework of natural cyclic tetra-peptide chlamydocin.The anti-breast cancer activity of the inhibitor was evaluated by CCK8,Hoechst staining,flow cytometry and scratch assay.Western blot method was used to initially explore the possible mechanism of action of the inhibitor.Results:Based on the mass spectrum result,we finally synthesized the novel cyclic tetra-peptide HDAC inhibitor.The inhibitor significantly inhibited the proliferation and migration of breast cancer cell lines T47D and MCF7.The IC50 of the cyclic tetra-peptide HDAC inhibitor for MCF7 and T47D was 3.0 nmol/L and 2.5 nmol/L,respectively.Cell apoptosis level was obviously enhanced after HDAC inhibitor treated cells.After treatment with the inhibitor,the expression level of APOE was up-regulated.In contrast,the expression levels of SREBP2 and HMGCR were reduced,suggesting the potential role of cyclic tetra-peptide HDAC inhibitor in lipid metabolism.Conclusion:A novel synthetic cyclic tetra-peptide HDAC inhibitor can effectively inhibit the proliferation and migration of breast cancer cells,which is expected to provide new therapeutic drugs for breast cancer treatment.