Michaelis Martin, Voges Yvonne, Rothweiler Florian, Weipert Fabian, Zia-Ahmad Amara, Cinatl Jaroslav, von Deimling Andreas, Westermann Frank, Rödel Franz, Wass Mark N, Cinatl Jindrich
Industrial Biotechnology Centre and School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK.
Institut für Medizinische Virologie, Goethe-Universität, 60596 Frankfurt am Main, Germany.
Cancers (Basel). 2020 Mar 2;12(3):577. doi: 10.3390/cancers12030577.
The survivin suppressant YM155 is a drug candidate for neuroblastoma. Here, we tested YM155 in 101 neuroblastoma cell lines (19 parental cell lines, 82 drug-adapted sublines). Seventy seven (77) cell lines displayed YM155 ICs in the range of clinical YM155 concentrations. ABCB1 was an important determinant of YM155 resistance. The activity of the ABCB1 inhibitor zosuquidar ranged from being similar to that of the structurally different ABCB1 inhibitor verapamil to being 65-fold higher. ABCB1 sequence variations may be responsible for this, suggesting that the design of variant-specific ABCB1 inhibitors may be possible. Further, we showed that ABCC1 confers YM155 resistance. Previously, p53 depletion had resulted in decreased YM155 sensitivity. However, -mutant cells were not generally less sensitive to YM155 than wild-type cells in this study. Finally, YM155 cross-resistance profiles differed between cells adapted to drugs as similar as cisplatin and carboplatin. In conclusion, the large cell line panel was necessary to reveal an unanticipated complexity of the YM155 response in neuroblastoma cell lines with acquired drug resistance. Novel findings include that ABCC1 mediates YM155 resistance and that YM155 cross-resistance profiles differ between cell lines adapted to drugs as similar as cisplatin and carboplatin.
存活素抑制剂YM155是一种用于治疗神经母细胞瘤的候选药物。在此，我们在101种神经母细胞瘤细胞系（19种亲本细胞系，82种药物适应亚系）中测试了YM155。77种细胞系显示YM155的半数抑制浓度（IC）处于临床YM155浓度范围内。ABCB1是YM155耐药性的一个重要决定因素。ABCB1抑制剂唑喹达的活性范围从与结构不同的ABCB1抑制剂维拉帕米相似到高出65倍。ABCB1序列变异可能对此负责，这表明设计针对变异体的ABCB1抑制剂可能是可行的。此外，我们表明ABCC1赋予YM155耐药性。此前，p53缺失导致YM155敏感性降低。然而，在本研究中，p53突变细胞通常并不比野生型细胞对YM155更不敏感。最后，适应顺铂和卡铂等相似药物的细胞之间，YM155的交叉耐药谱有所不同。总之，需要大量的细胞系面板来揭示具有获得性耐药性的神经母细胞瘤细胞系中YM155反应出人意料的复杂性。新发现包括ABCC1介导YM155耐药性，以及适应顺铂和卡铂等相似药物的细胞系之间YM155交叉耐药谱不同。
