Fechete Raul, Barth Susanne, Olender Tsviya, Munteanu Andreea, Bernthaler Andreas, Inger Aron, Perco Paul, Lukas Arno, Lancet Doron, Cinatl Jindrich, Michaelis Martin, Mayer Bernd
Emergentec Biodevelopment GmbH, Gersthofer Strasse 29-31, 1180 Vienna, Austria.
Mol Biosyst. 2011 Jan;7(1):200-14. doi: 10.1039/c0mb00082e. Epub 2010 Oct 28.
Chemotherapy of cancer experiences a number of shortcomings including development of drug resistance. This fact also holds true for neuroblastoma utilizing chemotherapeutics as vincristine. We performed a comparative analysis of molecular and cellular mechanisms associated with vincristine resistance utilizing cell line as well as human tissue data. Differential gene expression analysis revealed molecular features, processes and pathways afflicted with drug resistance mechanisms in general, and specifically with vincristine significantly involving actin associated features. However, specific mode of resistance as well as underlying genotype of parental, vincristine sensitive cells apparently exhibited significant heterogeneity. No consensus profile for vincristine resistance could be derived, but resistance-associated changes on the level of individual neuroblastoma cell lines as well as individual patient profiles became clearly evident. Based on these prerequisites we utilized the concept of synthetic lethality aimed at identifying hub proteins which when inhibited promise to induce cell death due to a synthetic lethal interaction with down-regulated, chemoresistance associated features. Our screening procedure identified synthetic lethal hub proteins afflicted with actin associated processes holding synthetic lethal interactions to down-regulated features individually found in all chemoresistant cell lines tested, therefore promising an improved therapeutic window. Verification of such synthetic lethal hub candidates in human neuroblastoma tissue expression profiles indicated the feasibility of this screening approach for addressing vincristine resistance in neuroblastoma.
癌症化疗存在许多缺点，包括耐药性的产生。对于使用长春新碱等化疗药物治疗的神经母细胞瘤来说，情况也是如此。我们利用细胞系以及人体组织数据，对与长春新碱耐药相关的分子和细胞机制进行了比较分析。差异基因表达分析揭示了一般耐药机制所涉及的分子特征、过程和通路，特别是与长春新碱耐药显著相关的肌动蛋白相关特征。然而，亲代长春新碱敏感细胞的具体耐药模式以及潜在基因型显然表现出显著的异质性。无法得出长春新碱耐药的一致特征，但单个神经母细胞瘤细胞系水平以及个体患者特征上与耐药相关的变化变得清晰可见。基于这些前提条件，我们利用合成致死的概念，旨在识别枢纽蛋白，当这些蛋白受到抑制时，有望由于与下调的、与化疗耐药相关的特征发生合成致死相互作用而诱导细胞死亡。我们的筛选程序确定了与肌动蛋白相关过程有关的合成致死枢纽蛋白，这些蛋白与在所有测试的化疗耐药细胞系中单独发现的下调特征存在合成致死相互作用，因此有望改善治疗窗口。在人类神经母细胞瘤组织表达谱中对这些合成致死枢纽候选蛋白进行验证，表明了这种筛选方法用于解决神经母细胞瘤长春新碱耐药问题的可行性。
