Acquired resistance to oxaliplatin is not directly associated with increased resistance to DNA damage in SK-N-ASrOXALI4000, a newly established oxaliplatin-resistant sub-line of the neuroblastoma cell line SK-N-AS.
Acquired resistance to oxaliplatin is not directly associated with increased resistance to DNA damage in SK-N-ASrOXALI4000, a newly established oxaliplatin-resistant sub-line of the neuroblastoma cell line SK-N-AS.
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DOI：
10.1371/journal.pone.0172140
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Michaelis M
中科院分区：
文献类型：
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作者：
Saintas E;Abrahams L;Ahmad GT;Ajakaiye AM;AlHumaidi AS;Ashmore-Harris C;Clark I;Dura UK;Fixmer CN;Ike-Morris C;Mato Prado M;Mccullough D;Mishra S;Schöler KM;Timur H;Williamson MD;Alatsatianos M;Bahsoun B;Blackburn E;Hogwood CE;Lithgow PE;Rowe M;Yiangou L;Rothweiler F;Cinatl J Jr;Zehner R;Baines AJ;Garrett MD;Gourlay CW;Griffin DK;Gullick WJ;Hargreaves E;Howard MJ;Lloyd DR;Rossman JS;Smales CM;Tsaousis AD;von der Haar T;Wass MN;Michaelis M
获得性耐药的形成是初治后抗癌治疗失败的主要原因。在这里，我们介绍了一种新的获得性奥沙利铂耐药模型，该模型是非MYCN扩增的神经母细胞瘤细胞系SK-N-AS的一个亚系，适合在4000 ng/mL奥沙利铂存在下生长(SK-N-ASrOXALI4000)。24条染色体荧光原位杂交显示，SK-N-ASrOXALI4000细胞的染色体畸变率高于SK-N-AS细胞。此外，SK-N-ASrOXALI4000细胞不仅对奥沙利铂耐药，而且对另外两种常用的抗癌铂类药物顺铂和卡铂也有耐药性。SK-N-ASrOXALI4000细胞表现出稳定的耐药表型，在没有奥沙利铂的情况下培养10周不会影响其耐药表型。有趣的是，SK-N-ASrOXALI4000细胞对吉西他滨没有交叉耐药性，对阿霉素和紫外线辐射的敏感性增加，这两种替代疗法像铂类药物一样针对DNA完整性。值得注意的是，UVC诱导的DNA损伤被认为主要通过核苷酸切除修复，而核苷酸切除修复一直被描述为奥沙利铂诱导的DNA损伤修复的主要系统。SK-N-ASrOXALI4000细胞对甲型流感病毒的裂解也比SK-N-AS细胞更敏感，甲型流感病毒是一种候选的溶瘤药物。综上所述，我们引入了一种新的奥沙利铂耐药模型。奥沙利铂在SK-N-ASrOXALI4000细胞中的耐药机制似乎很复杂，并不直接依赖于增强的DNA修复能力。奥沙利铂耐药模型具有特别重要的意义，因为到目前为止，铂类药物的研究主要集中在顺铂和卡铂上。
The formation of acquired drug resistance is a major reason for the failure of anti-cancer therapies after initial response. Here, we introduce a novel model of acquired oxaliplatin resistance, a sub-line of the non-MYCN-amplified neuroblastoma cell line SK-N-AS that was adapted to growth in the presence of 4000 ng/mL oxaliplatin (SK-N-ASrOXALI4000). SK-N-ASrOXALI4000 cells displayed enhanced chromosomal aberrations compared to SK-N-AS, as indicated by 24-chromosome fluorescence in situ hybridisation. Moreover, SK-N-ASrOXALI4000 cells were resistant not only to oxaliplatin but also to the two other commonly used anti-cancer platinum agents cisplatin and carboplatin. SK-N-ASrOXALI4000 cells exhibited a stable resistance phenotype that was not affected by culturing the cells for 10 weeks in the absence of oxaliplatin. Interestingly, SK-N-ASrOXALI4000 cells showed no cross resistance to gemcitabine and increased sensitivity to doxorubicin and UVC radiation, alternative treatments that like platinum drugs target DNA integrity. Notably, UVC-induced DNA damage is thought to be predominantly repaired by nucleotide excision repair and nucleotide excision repair has been described as the main oxaliplatin-induced DNA damage repair system. SK-N-ASrOXALI4000 cells were also more sensitive to lysis by influenza A virus, a candidate for oncolytic therapy, than SK-N-AS cells. In conclusion, we introduce a novel oxaliplatin resistance model. The oxaliplatin resistance mechanisms in SK-N-ASrOXALI4000 cells appear to be complex and not to directly depend on enhanced DNA repair capacity. Models of oxaliplatin resistance are of particular relevance since research on platinum drugs has so far predominantly focused on cisplatin and carboplatin.