title: CYP1B1 enhances the resistance of epithelial ovarian cancer cells to paclitaxel in vivo and in vitro.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Shanxi Datong University School of Medicine, Datong, Shanxi 037009, P.R. China.
authors.forename: Zhuangyan
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Institute of Immunology, Shanxi Datong University School of Medicine, Datong, Shanxi 037009, P.R. China.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Mu
authors.affiliation: Institute of Immunology, Shanxi Datong University School of Medicine, Datong, Shanxi 037009, P.R. China.
authors.forename: Caixia
authors.initials: C
authors.lastname: Qi
authors.affiliation: Institute of Immunology, Shanxi Datong University School of Medicine, Datong, Shanxi 037009, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Immunology, Shanxi Datong University School of Medicine, Datong, Shanxi 037009, P.R. China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Xi
authors.affiliation: Institute of Immunology, Shanxi Datong University School of Medicine, Datong, Shanxi 037009, P.R. China.
authors.forename: Juncheng
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Obstetrics and Gynecology, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China.
authors.forename: Ruoran
authors.initials: R
authors.lastname: Mi
authors.affiliation: Institute of Immunology, Shanxi Datong University School of Medicine, Datong, Shanxi 037009, P.R. China.
authors.forename: Fuxi
authors.initials: F
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D065633:Cytochrome P-450 CYP1B1 / Q000096:biosynthesis* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D064593:Heterografts; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D017239:Paclitaxel