Abstract：
Breast cancer (BC) is one of the most diagnosed cancers in women. Recently, a promising target for BC treatment was found in kinesin Eg5, a mitotic motor protein that allows bipolar spindle formation and cell replication. Thus, the aim of this work was to evaluate the effects of novel thiadiazoline-based Eg5 inhibitors, analogs of K858, in an in vitro model of BC (MCF7 cell line). Compounds 2 and 41 were selected for their better profile as they reduce MCF7 viability at lower concentrations and with minimal effect on non-tumoral cells with respect to K858. Compounds 2 and 41 counteract MCF7 migration by negatively modulating the NF-kB/MMP-9 pathway. The expression of HIF-1α and VEGF appeared also reduced by 2 and 41 administration, thus preventing the recruitment of the molecular cascade involved in angiogenesis promotion. In addition, 2 provokes an increased caspase-3 activation thus triggering the MCF7 apoptotic event, while 41 and K858 seem to induce the necrosis axis, as disclosed by the increased expression of PARP. These results allow us to argue that 2 and 41 are able to simultaneously intervene on pivotal molecular signaling involved in breast cancer progression, leading to the assumption that Eg5 inhibition can represent a valid approach to counteract BC progression.
摘要：
乳腺癌（BC）是女性诊断最多的癌症之一。最近,在驱动蛋白Eg5中发现了BC治疗的一个有希望的靶标，Eg5是一种有丝分裂运动蛋白，允许双极纺锤体形成和细胞复制。因此，这项工作的目的是评估基于噻二唑啉的新型Eg5抑制剂的作用，K858的类似物，在BC（MCF7细胞系）的体外模型中。选择化合物2和41的较好特征,因为它们在较低浓度下降低MCF7活力,并且相对于K858对非肿瘤细胞的影响最小。化合物2和41通过负调节NF-kB/MMP-9途径来抵消MCF7迁移。2次和41次给药,HIF-1α和VEGF的表达也出现降低,从而防止参与血管生成促进的分子级联的募集。此外,2引起caspase-3激活增加，从而触发MCF7凋亡事件，而41和K858似乎诱导了坏死轴，正如PARP表达增加所揭示的。这些结果使我们认为2和41能够同时干预参与乳腺癌进展的关键分子信号，导致假设Eg5抑制可以代表抵消BC进展的有效方法。
