Zhu Zhuangyan, Mu Yaqin, Qi Caixia, Wang Jian, Xi Guoping, Guo Juncheng, Mi Ruoran, Zhao Fuxi
Department of Obstetrics and Gynecology, Shanxi Datong University School of Medicine, Datong, Shanxi 037009, P.R. China.
Institute of Immunology, Shanxi Datong University School of Medicine, Datong, Shanxi 037009, P.R. China.
Int J Mol Med. 2015 Feb;35(2):340-8. doi: 10.3892/ijmm.2014.2041. Epub 2014 Dec 16.
Ovarian cancer (OC) is the most frequent cause of mortality among gynecological malignancies, with a 5-year survival rate of approximately 30%. The standard regimen for OC therapy includes a platinum agent combined with a taxane, to which the patients frequently acquire resistance. Resistance arises from the oxidation of anticancer drugs by CYP1B1, a cytochrome P450 enzyme overexpressed in malignant OC. The aim of the present study was to determine the role of CYP1B1 expression in the drug resistance of OC to the taxane, paclitaxel (PTX). Immunohistochemical staining was used to assess CYP1B1 expression in a panel of ovarian samples (53 primary cancer samples, 14 samples of metastastic cancer, 30 benign tumor samples and 19 normal tissue samples). Semi-quantitative RT-PCR was also performed to determine CYP1B1 expression in several OC cell lines. Finally, we used proliferation and toxicity assays, as well as a mouse xenograft model using nude mice to determine whether α-naphthoflavone (ANF), a CYP1B1 specific inhibitor, reduces resistance to PTX. CYP1B1 was overexpressed in the samples from primary and metastatic loci of epithelial ovarian cancers. In some cell lines, PTX induced CYP1B1 expression, which resulted in drug resistance. Exposure to ANF reduced drug resistance and enhanced the sensitivity of OC cells to PTX in vitro and in vivo. The expression profile of CYP1B1 suggests that it has the potential to be a useful diagnostic marker and prognostic factor for malignant OC. The inhibition of CYP1B1 expression by specific agents may provide a novel therapeutic strategy for the treatment of patients resistant to PTX and may improve the prognosis of these patients.
卵巢癌（OC）是妇科恶性肿瘤中最常见的死亡原因，5年生存率约为30%。OC治疗的标准方案包括铂类药物联合紫杉烷，患者对此常产生耐药性。耐药性源于细胞色素P450酶CYP1B1对抗癌药物的氧化作用，CYP1B1在恶性OC中过表达。本研究的目的是确定CYP1B1表达在OC对紫杉烷紫杉醇（PTX）耐药性中的作用。采用免疫组织化学染色评估一组卵巢样本（53例原发性癌样本、14例转移性癌样本、30例良性肿瘤样本和19例正常组织样本）中CYP1B1的表达。还进行了半定量逆转录聚合酶链反应以确定几种OC细胞系中CYP1B1的表达。最后，我们使用增殖和毒性试验以及裸鼠异种移植模型来确定CYP1B1特异性抑制剂α-萘黄酮（ANF）是否能降低对PTX的耐药性。CYP1B1在上皮性卵巢癌原发和转移部位的样本中过表达。在一些细胞系中，PTX诱导CYP1B1表达，从而导致耐药性。在体外和体内，接触ANF可降低耐药性并增强OC细胞对PTX的敏感性。CYP1B1的表达谱表明它有可能成为恶性OC的有用诊断标志物和预后因素。通过特异性药物抑制CYP1B1表达可能为治疗对PTX耐药的患者提供一种新的治疗策略，并可能改善这些患者的预后。
