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Abstract：
Natural products are a valuable source of new molecules and are important for drug discovery. Many chemotherapeutics currently in clinical use were originated from natural sources and are effective cytotoxic agents. In this study, we investigated the cytotoxic and pro-apoptotic effects of achyrobichalcone (ACB) and 3-O-methylquercetin (3OMQ), two novel compounds isolated from the Achyrocline satureioides plant. Because extracts from this plant have been shown to have anticancer activity in vitro, we evaluated ACB and 3OMQ using a human breast cancer cell line, MDA-MB-231, and a nontumorigenic human breast epithelial cell line, MCF-12A. We found that ACB demonstrates cytotoxic effects on MDA-MB-231 cells, but not MCF-12A cells. 3OMQ also demonstrated cytotoxic effects on MDA-MB-231 cells, but with lower selectivity compared to treated MCF-12A cells. Cell death by both compounds was associated with caspase-9 and caspase-3/7 activation. Using high-resolution respirometry, we found that ACB and 3OMQ were able to cause acute mitochondrial dysfunction in MDA-MB-231-treated cells. These results suggest that apoptosis in MDA-MB-231 cells is induced through the activation of the mitochondrial-dependent pathway. Collectively, these findings suggest that ACB is a strong candidate for further anticancer in vivo tests.
摘要：
天然产物是新分子的宝贵来源，对药物发现很重要。目前在临床上使用的许多化学治疗剂源自天然来源并且是有效的细胞毒性剂。在这项研究中,我们研究了细胞毒性和促凋亡作用的速曲酮（ACB）和3-O-甲基槲皮素（3OMQ），从Achyroclinesatureioides植物中分离出两个新化合物。因为这种植物的提取物已被证明在体外具有抗癌活性，我们使用人乳腺癌细胞系评估了ACB和3OMQ，MDA-MB-231和一种非致瘤的人乳腺上皮细胞系，MCF-12A。我们发现ACB对MDA-MB-231细胞具有细胞毒性作用，但不是MCF-12A细胞。3OMQ还证明了对MDA-MB-231细胞的细胞毒性作用，但与处理的MCF-12A细胞相比选择性较低。两种化合物的细胞死亡与胱天蛋白酶-9和胱天蛋白酶-3/7活化相关。使用高分辨率呼吸测量法，我们发现ACB和3OMQ能够在MDA-MB-231处理的细胞中引起急性线粒体功能障碍。这些结果表明，MDA-MB-231细胞的凋亡是通过激活线粒体依赖性途径诱导的。总的来说，这些发现表明ACB是进一步体内抗癌试验的有力候选者.
