PLoS ONE：P-糖蛋白调节卵巢癌细胞耐药性

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在一项新研究中，爱尔兰都柏林圣三一学院(Trinity College Dublin)研究了耐药性卵巢癌细胞。这些研究发现最近发表在<em>PLoS ONE</em>期刊上，将有助于人们理解耐药性卵巢癌中的分子标记物以便改善临床治疗。

对包括卵巢癌在内的很多癌症而言，化疗仍然是唯一的治疗选择。尽管化疗能够获得成功的疗效，但是大多数卵巢癌病人最后对化疗产生耐药性。确定给病人服用哪种化疗药物是一种复杂的过程。人们作出的大多数决策基于病人所患的癌症类型和癌症的进展程度。当前，人们正转向对每名病人进行个人化修饰的化疗治疗。

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这项研究研究了被称作IGROVCDDP的耐药性卵巢癌细胞。IGROV-1细胞最初从是一名卵巢癌病人体内获得的。在实验室中，IGROV-1细胞经过数轮化疗治疗来模拟癌症病人在诊断中接受的治疗。IGROV-1细胞产生的子细胞就是IGROVCDDP细胞，这些细胞在组织培养中进行培养，并且被用来研究它们如何产生耐药性。

IGROVCDDP细胞对用于卵巢癌一线治疗的两种化疗药物---顺铂(cisplatin)和紫杉醇(paclitaxel)---产生耐药性。通过研究这些IGROVCDDP细胞，研究人员能够鉴定出哪些基因和蛋白发生改变，和在诊所内可能作为化疗耐药性的分子标记物。IGROVCDDP细胞有很多化疗耐药性的分子标记物，并且突出强调耐药性癌细胞中能够同时存在的多种机制。IGROVCDDP细胞拥有水平增加的药物外排泵(drug-efflux pump)，即P-糖蛋白(P-glycoprotein)。通过将紫杉醇泵出这种癌细胞之外，这就导致对这种药物产生耐药性。这项研究突出强调了P-糖蛋白能够与多种对顺铂产生耐药性的机制共同存在。对顺铂产生耐药性部分上是由谷胱甘肽途径和癌细胞降低对这种药物的摄取所调节的。这些发现是朝理解卵巢癌病人体内耐药性分子标记物如何相互作用和重叠的目标上迈出了一步。

本文编译自<a href="http://medicalxpress.com/news/2012-08-drug-resistant-ovarian-cancer-clinical.html" target="_blank">Researchers investigate drug resistant ovarian cancer to improve clinical treatment</a>
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<a title="" href="http://dx.doi.org/10.1371/journal.pone.0040717" target="_blank">doi: 10.1371/journal.pone.0040717</a>
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<br/><strong>Resistance to Paclitaxel in a Cisplatin-Resistant Ovarian Cancer Cell Line Is Mediated by P-Glycoprotein</strong><br/>


Britta Stordal1,2*, Marion Hamon1, Victoria McEneaney2, Sandra Roche1, Jean-Pierre Gillet3, John J. O’Leary2, Michael Gottesman3, Martin Clynes

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.

<br/>来源：生物谷

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