Department of Oncology, Montefiore Medical Center, Bronx, NY, USA.
Anticancer Res. 2010 Jul;30(7):2531-8.
Oxaliplatin is used to treat patients with colorectal cancer (CRC); however, half the patients fail to benefit. The excision repair cross-complementing group-1 (ERCC1) gene was studied and it was hypothesized that its inducible expression contributes to cellular resistance.
Thirty CRC cell lines were treated with oxaliplatin and sensitivity was determined by apoptosis. Four sensitive and resistant cell lines were analyzed for oxaliplatin effect on ERCC1 expression and two resistant cell lines were subjected to siRNA-mediated gene silencing.
There was no correlation of basal ERCC1 mRNA expression with response to oxaliplatin. ERCC1 mRNA was induced at 24, 48, and 72 hours (71-264%, p<0.05) and ERCC1 protein at 48 hours (123-521%, p<0.05) post-oxaliplatin treatment in resistant cells only. siRNA-mediated silencing of ERCC1 sensitized the CRC cells to oxaliplatin-induced apoptosis, and increased cleaved PARP.
ERCC1 gene expression is inducible, contributes to oxaliplatin resistance, and is reversible by targeted suppression of ERCC1, identifying ERCC1 as a potential target for drug development.
奥沙利铂用于治疗结直肠癌（CRC）患者；然而，半数患者未能从中获益。切除修复交叉互补基因 1（ERCC1）基因已被研究，其假设诱导表达有助于细胞耐药性。
用奥沙利铂处理 30 种 CRC 细胞系，并通过细胞凋亡测定敏感性。分析了 4 种敏感和耐药细胞系奥沙利铂对 ERCC1 表达的影响，并用 siRNA 介导的基因沉默处理了 2 种耐药细胞系。
基础 ERCC1 mRNA 表达与奥沙利铂的反应无相关性。仅在耐药细胞中，奥沙利铂处理后 24、48 和 72 小时（71-264%，p<0.05）诱导 ERCC1 mRNA 表达，48 小时（123-521%，p<0.05）诱导 ERCC1 蛋白表达。ERCC1 的 siRNA 介导沉默使 CRC 细胞对奥沙利铂诱导的细胞凋亡敏感，并增加了 PARP 的裂解。
ERCC1 基因表达可诱导，有助于奥沙利铂耐药，通过靶向抑制 ERCC1 是可逆的，这表明 ERCC1 是药物开发的潜在靶点。
