Drug-induced mitochondrial oxidative stress is responsible for various effects of the survivin inhibitor Sepantronium Bromide (YM155) in triple negative breast cancer cells

Sepantronium bromide (YM155), a transcriptional inhibitor of anti-apoptotic protein survivin, is considered as a potential drug candidate for triple negative breast cancers (TNBC). Regardless of its excellent performance in pre-clinical models of TNBC, in patients, this drug was unable to outperform the standard chemotherapy docetaxel. The goal of this study was to identify the pathways/molecules affected by YM155 in TNBC cell lines. Detailed biochemical analysis of the paired YM155-sensitive and resistant cell lines indicates that induction of mitochondrial oxidative stress is a first-line response to the drug, ultimately leading to growth inhibition and induction of cell death. Multiple pathways involved in dampening oxidative stress-induced damages are differentially regulated in YM155-resistant cells. Furthermore, the emergence of YM155 resistance is associated with an extensive transcriptional reprogramming and alteration of many more biological pathways in addition to those identified by biochemical assays. Molecules associated with these biological pathways will potentially serve as biomarkers predicting YM155 sensitivity in TNBC cells. Two biological replicates were analyzed for each of samples (Sensitive and Resistant)

溴代塞潘托宁（Sepantronium bromide，YM155）是一种靶向抗凋亡蛋白生存素（survivin）的转录抑制剂，被视为三阴性乳腺癌（triple negative breast cancers, TNBC）的潜在候选治疗药物。尽管其在三阴性乳腺癌临床前模型中展现出优异活性，但在临床患者中，该药物并未展现出优于标准化疗药物多西他赛的疗效。本研究旨在明确YM155在三阴性乳腺癌细胞系中所影响的通路与分子。通过对成对的YM155敏感与耐药细胞系开展详细生化分析，研究发现线粒体氧化应激的诱导是该药物的初始应答反应，最终可导致细胞生长抑制与细胞死亡的诱发。多种参与缓解氧化应激诱导损伤的通路在YM155耐药细胞中呈现差异调控特征。此外，YM155耐药性的产生与广泛的转录重编程相关，且除生化实验所鉴定的通路外，还会改变更多的生物学通路。与上述生物学通路相关的分子，有望作为预测三阴性乳腺癌细胞对YM155敏感性的生物标志物。本研究对敏感组与耐药组的每个样本均设置了两次生物学重复。