Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan.
Int J Oncol. 2011 Feb;38(2):513-9. doi: 10.3892/ijo.2010.866. Epub 2010 Dec 7.
Gemcitabine is an effective chemotherapy against non-small cell lung cancer (NSCLC). However, resistance to gemcitabine reduces its efficacy. We have isolated gemcitabine-resistant human non-small cell lung cancer A549 cells, termed A549/GR cells. A549/GR cells were resistant to gemcitabine as well as paclitaxel and docetaxel but not carboplatin and irinotecan. The expression level of multidrug resistance protein 7 (MRP7) in A549/GR cells was higher than that in A549 cells, and the inhibitor of MRP7 by cepharanthine increased the sensitivity to gemcitabine in A549/GR cells. These findings indicate that cepharanthine reversed gemcitabine resistance. To determine predictive molecular markers of gemcitabine resistance for more effective treatment of these tumors, we performed PCR array. We identified that CDKN1A/p21, CYP3A5, microsomal epoxide hyrolase 1 (EPHX1) and ABCC6 (MRP6) were up-regulated >5-fold in A549/GR cells. Gemcitabine also induced the expression of p21 and CYP3A5 in A549 cells. A better understanding of the characterization and mechanism of the resistance to gemcitabine in A549/GR cells may help identify agents that reverse clinical gemcitabine resistance in NSCLC.
吉西他滨是一种有效的非小细胞肺癌（NSCLC）化疗药物。然而，吉西他滨耐药会降低其疗效。我们已经分离出对吉西他滨耐药的人非小细胞肺癌 A549 细胞，称为 A549/GR 细胞。A549/GR 细胞对吉西他滨以及紫杉醇和多西他赛耐药，但对卡铂和伊立替康不耐药。A549/GR 细胞中多药耐药蛋白 7（MRP7）的表达水平高于 A549 细胞，而 MRP7 的抑制剂芹菜甲素增加了 A549/GR 细胞对吉西他滨的敏感性。这些发现表明芹菜甲素逆转了吉西他滨耐药性。为了确定吉西他滨耐药的预测性分子标志物，以更有效地治疗这些肿瘤，我们进行了 PCR 阵列分析。我们发现 CDKN1A/p21、CYP3A5、微粒体环氧化物水解酶 1（EPHX1）和 ABCC6（MRP6）在 A549/GR 细胞中上调超过 5 倍。吉西他滨也诱导了 A549 细胞中 p21 和 CYP3A5 的表达。更好地了解 A549/GR 细胞对吉西他滨耐药的特征和机制，可能有助于确定逆转 NSCLC 临床吉西他滨耐药的药物。
