title: Isolation and characterization of gemcitabine-resistant human non-small cell lung cancer A549 cells.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Ikeda
authors.forename: Lee C
authors.initials: LC
authors.lastname: Vermeulen
authors.forename: Elim
authors.initials: E
authors.lastname: Lau
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Jiang
authors.forename: Kamakshi
authors.initials: K
authors.lastname: Sachidanandam
authors.forename: Katsushi
authors.initials: K
authors.lastname: Yamada
authors.forename: Jill M
authors.initials: JM
authors.lastname: Kolesar
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D003841:Deoxycytidine; D000093542:Gemcitabine