National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
PLoS One. 2012;7(7):e40717. doi: 10.1371/journal.pone.0040717. Epub 2012 Jul 11.
The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy.
IGROVCDDP 顺铂耐药卵巢癌细胞系也对紫杉醇耐药，并模拟了一线铂类/紫杉烷化疗后复发卵巢癌患者的耐药表型。使用 TaqMan 低密度阵列 (TLDA) 来描述与 IGROVCDDP 细胞中化疗耐药相关的 380 个基因的表达。IGROVCDDP 中的紫杉醇耐药是通过 P-糖蛋白的基因和蛋白过表达介导的，并且该蛋白具有功能活性。顺铂耐药不能被 elacridar 逆转，证实顺铂不是 P-糖蛋白的底物。IGROVCDDP 中的顺铂耐药是多因素的，部分由谷胱甘肽途径和药物蓄积减少介导。总细胞谷胱甘肽没有增加。然而，GSR 和 GGT1 的酶活性上调。铜转运蛋白 CTR1 的细胞定位从 IGROV-1 的膜相关变为 IGROVCDDP 的细胞质。这可能介导了先前报道的蓄积缺陷。钠钾泵 (ATP1A)、MRP1 和 FBP 的表达减少，这些都与铂耐药细胞系中铂蓄积缺陷有关。MRP1 的细胞定位在 IGROVCDDP 中也发生改变，从 IGROV-1 的基底外侧转移。BRCA1 的基因和蛋白水平也上调。在使用顺铂建立的耐药模型中 P-糖蛋白的过度表达是不寻常的。这表明 P-糖蛋白可以作为一种普遍的应激反应而上调，而不是作为对底物的特异性反应。在 IGROVCDDP 细胞中表征的机制可能适用于接受一线铂类/紫杉烷化疗的复发卵巢癌患者。
