Novel Poly(ADP-ribose) Polymerase-1 Inhibitor DDHCB Inhibits Proliferation of BRCA Mutant Breast Cancer Cell In Vitro and In Vivo through a Synthetic Lethal Mechanism.
Novel Poly(ADP-ribose) Polymerase-1 Inhibitor DDHCB Inhibits Proliferation of BRCA Mutant Breast Cancer Cell In Vitro and In Vivo through a Synthetic Lethal Mechanism.
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新型聚（ADP-核糖）聚合酶-1 抑制剂 DDHCB 通过合成致死机制在体外和体内抑制 BRCA 突变乳腺癌细胞的增殖。
DOI：
10.1021/acs.chemrestox.0c00087
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发表时间：
2020
影响因子：
4.1
通讯作者：
Guo Chuanlong
中科院分区：
文献类型：
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作者：
Wang Lijun;Zhang Shuhong;Yu Xuemin;Guo Chuanlong
聚（adp -核糖）聚合酶-1 （PARP-1）抑制剂是有效用于治疗乳腺癌的药物。合成了一种新型溴酚衍生物乙基(E)-4-（2-（2,3-二溴-4,5-二甲氧基苄基）肼-1-碳硫氨基）苯甲酸酯（DDHCB）作为新型PARP-1抑制剂。我们的研究发现，DDHCB可以抑制PARP-1活性，ic50值为58.3 nM。3-（4,5-二甲基噻唑-2-基）-2,5-二苯-尼基溴化四唑（MTT）试验表明，DDHCB可选择性抑制BRCA突变细胞的增殖，并具有合成致死性。DDHCB还能诱导DNA双链断裂，并能增加γ-H2AX的聚焦量。此外，DDHCB可以增加HCC-1937细胞中PARP-1-DNA的捕获，抑制PAR的形成。进一步研究发现，DDHCB可诱导细胞凋亡和G2/M周期阻滞。最后，我们发现DDHCB对HCC-1937异种移植物生长有抑制作用，且毒性较低。体内机制显示，在ddhcb处理的肿瘤中，γ-H2AX水平升高，表明DDHCBin在体内具有抑制PARP-1的能力。我们的研究结果表明，DDHCB治疗乳腺癌的未来发展是有希望的。
Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors are drugs that are effectively used to treat breast cancer. We synthesized a novel bromophenol derivative ethyl (E)-4-(2-(2,3-dibromo-4,5-dimethoxybenzylidene)hydrazine-1-carbothioamido)benzoate (DDHCB) as a novel PARP-1 inhibitor. Our study found that DDHCB could inhibit PARP-1 activity with an IC50value of 58.3 nM. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphe-nyltetrazolium bromide (MTT) assay indicated that DDHCB could selectively inhibit proliferation of BRCA mutant cells and demonstrate the ability of synthetic lethality. DDHCB could also induce DNA double-strand breaks with the ability to increase the foci quantitation of γ-H2AX. Moreover, DDHCB could increase PARP-1-DNA trapping and inhibit PAR formation in HCC-1937 cells. Further investigation showed that DDHCB induced apoptosis and G2/M cycle arrest. Finally, we found that DDHCB inhibited the growth of HCC-1937 xenografts with low toxicity.In vivomechanisms showed that the level of γ-H2AX was increased in the DDHCB-treated tumors, indicating the PARP-1 inhibition ability of DDHCBin vivo. Our study results indicated that the future development of DDHCB for the treatment of breast cancer is promising.