本文报道了一组具有强细胞毒性的丙炔酸氨基甲酰甲酯(PACMAs)，它们能有效抑制多种癌细胞系的增殖，并诱导早期和晚期凋亡。代表性化合物在MDA-MB-435小鼠异种移植模型中抑制肿瘤生长且无明显毒性。研究通过Kinexus628抗体微阵列和Ingenuity Pathway Analysis揭示了化合物1通过调节SOD1和STIP1表达启动Nrf2介导的氧化应激。进一步通过测量线粒体超氧化物水平验证了氧化应激途径的参与。这是PACMAs作为抗肿瘤剂的首次报告，其广泛的体外细胞毒性、可能通过氧化应激介导的途径及体内疗效值得进一步的临床前研究。
摘要：
Herein, we discovered a series of propynoic acid carbamoyl methyl-amides (PACMAs) with potent cytotoxicity against a panel of cancer cell lines. These compounds interrupted cell cycle progression at low micromolar concentrations and induced early and late stage apoptosis. A representative compound suppressed tumor growth without apparent toxicity in an MDA-MB-435 mouse xenograft model. We used a Kinexus 628-antibody microarray and the Ingenuity Pathway Analysis (IPA) bioinformatics tools to better understand their mechanisms. The IPA analysis revealed the initiation of Nrf2-mediated oxidative stress through modulating the expression of SOD1 and STIP1 by compound 1. The involvement of the oxidative stress pathway was further validated by measuring the levels of the PACMA-induced mitochondrial superoxide species. To our knowledge, this is the first report on the discovery and biological evaluations of PACMAs as anticancer agents. Their broad-spectrum in vitro cytotoxicity, possibly through an oxidative stress-mediated pathway, and in vivo efficacy warrant further preclinical investigations.
展开
扫一扫
被折叠的 条评论
为什么被折叠?
到【灌水乐园】发言
