Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain.
Molecular Medicine Unit, Department of Medicine, University of Salamanca, 37007 Salamanca, Spain.
Int J Mol Sci. 2022 Oct 27;23(21):13019. doi: 10.3390/ijms232113019.
Ovarian cancer (OC) is one of the most common gynecologic neoplasia and has the highest mortality rate, which is mainly due to late-stage diagnosis and chemotherapy resistance. There is an urgent need to explore new and better therapeutic strategies. We have previously described a family of Microtubule Destabilizing Sulfonamides (MDS) that does not trigger multidrug-mediated resistance in OC cell lines. MDS bind to the colchicine site of tubulin, disrupting the microtubule network and causing antiproliferative and cytotoxic effects. In this work, a novel microtubule-destabilizing agent () was synthetized and characterized. This compound also inhibited OC cell proliferation and induced G2/M cell cycle arrest and apoptosis. Interestingly, was significantly more cytotoxic than MDS. Here, we also analyzed the effect of these microtubule-destabilizing agents (MDA) in combination with Panobinostat, a pan-histone deacetylase inhibitor. We found that Panobinostat synergistically enhanced MDA-cytotoxicity. Mechanistically, we observed that Panobinostat and MDA induced α-tubulin acetylation and that the combination of both agents enhanced this effect, which could be related to the observed synergy. Altogether, our results suggest that MDA/Panobinostat combinations could represent new therapeutic strategies against OC.
卵巢癌（OC）是最常见的妇科肿瘤之一，死亡率最高，主要是由于诊断晚期和化疗耐药。迫切需要探索新的更好的治疗策略。我们之前描述了一类微管不稳定磺胺类药物（MDS），它们不会在 OC 细胞系中引发多药介导的耐药性。MDS 与微管蛋白的秋水仙碱结合位点结合，破坏微管网络，导致抗增殖和细胞毒性作用。在这项工作中，合成并表征了一种新型的微管不稳定剂 ()。该化合物还抑制 OC 细胞增殖，并诱导 G2/M 细胞周期阻滞和细胞凋亡。有趣的是，与 MDS 相比， 具有更高的细胞毒性。在这里，我们还分析了这些微管稳定剂（MDA）与 Panobinostat（一种组蛋白去乙酰化酶抑制剂）联合使用的效果。我们发现 Panobinostat 与 MDA 协同增强了 MDA 的细胞毒性。从机制上讲，我们观察到 Panobinostat 和 MDA 诱导 α-微管蛋白乙酰化，并且两种药物的组合增强了这种作用，这可能与观察到的协同作用有关。总之，我们的结果表明，MDA/Panobinostat 联合可能代表针对 OC 的新的治疗策略。
