Rauch Anke, Hennig Dorle, Schäfer Claudia, Wirth Matthias, Marx Christian, Heinzel Thorsten, Schneider Günter, Krämer Oliver H
Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Hans-Knöll-Straße 2, 07745 Jena, Germany.
II Department of Internal Medicine, Technical University of Munich, Munich, Germany.
Biochim Biophys Acta. 2014 Apr;1845(2):202-20. doi: 10.1016/j.bbcan.2014.01.003. Epub 2014 Jan 16.
Survivin belongs to the family of apoptosis inhibitors (IAPs), which antagonizes the induction of cell death. Dysregulated expression of IAPs is frequently observed in cancers, and the high levels of survivin in tumors compared to normal adult tissues make it an attractive target for pharmacological interventions. The small imidazolium-based compound YM155 has recently been reported to block the expression of survivin via inhibition of the survivin promoter. Recent data, however, question that this is the sole and main effect of this drug, which is already being tested in ongoing clinical studies. Here, we critically review the current data on YM155 and other new experimental agents supposed to antagonize survivin. We summarize how cells from various tumor entities and with differential expression of the tumor suppressor p53 respond to this agent in vitro and as murine xenografts. Additionally, we recapitulate clinical trials conducted with YM155. Our article further considers the potency of YM155 in combination with other anti-cancer agents and epigenetic modulators. We also assess state-of-the-art data on the sometimes very promiscuous molecular mechanisms affected by YM155 in cancer cells.
生存素属于凋亡抑制蛋白（IAPs）家族，可拮抗细胞死亡的诱导。IAPs表达失调在癌症中经常可见，与正常成人组织相比，肿瘤中生存素的高水平使其成为药物干预的一个有吸引力的靶点。最近有报道称，基于咪唑鎓的小分子化合物YM155可通过抑制生存素启动子来阻断生存素的表达。然而，最近的数据对这是否是该药物的唯一主要作用提出了质疑，该药物已在正在进行的临床研究中进行测试。在此，我们批判性地回顾了关于YM155以及其他有望拮抗生存素的新型实验药物的现有数据。我们总结了来自各种肿瘤实体且肿瘤抑制因子p53表达不同的细胞在体外以及作为小鼠异种移植模型时对该药物的反应。此外，我们概括了使用YM155进行的临床试验。我们的文章还考虑了YM155与其他抗癌药物和表观遗传调节剂联合使用的效力。我们还评估了关于YM155在癌细胞中影响的有时非常混杂的分子机制的最新数据。
