title: Analysis of MDR genes expression and cross-resistance in eight drug resistant ovarian cancer cell lines.
abstract: BACKGROUND
  Multiple drug resistance (MDR) of cancer cells is the main reason of intrinsic or acquired insensitivity to chemotherapy in many cancers. In this study we used ovarian cancer model of acquired drug resistance to study development of MDR. We have developed eight drug resistant cell lines from A2780 ovarian cancer cell line: two cell lines resistant to each drug commonly used in ovarian cancer chemotherapy: cisplatin (CIS), paclitaxel (PAC), doxorubicin (DOX) and topotecan (TOP). A chemosensitivity assay - MTT was performed to assess drug cross-resistance. Quantitative real-time polymerase chain reaction and immunofluorescence were also performed to determine mRNA and protein expression of genes/proteins involved in drug resistance (P-gp, BCRP, MRP1, MRP2, MVP). Flow cytometry was used to determine the activity of drug transporters.
  
  
  RESULTS
  We could observe cross-resistance between PAC- and DOX-resistant cell lines. Additionally, both PAC-resistant cell lines were cross-resistant to TOP and both TOP-resistant cell lines were cross-resistant to DOX. We observed two different mechanisms of resistance to TOP related to P-gp and BCRP expression and activity. P-gp and BCRP were also involved in DOX resistance. Expression of MRP2 was increased in CIS-resistant cell lines and increased MVP expression was observed in CIS-, PAC- and TOP-, but not in DOX-resistant cell lines.
  
  
  CONCLUSIONS
  Effectiveness of TOP and DOX in second line of chemotherapy in ovarian cancer can be limited because of their cross-resistance to PAC. Moreover, cross-resistance of PAC-resistant cell line to CIS suggests that such interaction between those drugs might also be probable in clinic.
authors.affiliation: Department of Histology and Embryology, Poznan University of Medical Sciences, Swiecickiego 6 St., 61-781, Poznan, Poland. rjanuchowski@ump.edu.pl.
authors.forename: Radosław
authors.initials: R
authors.lastname: Januchowski
authors.affiliation: Department of Histology and Embryology, Poznan University of Medical Sciences, Swiecickiego 6 St., 61-781, Poznan, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Sterzyńska
authors.affiliation: Department of Histology and Embryology, Poznan University of Medical Sciences, Swiecickiego 6 St., 61-781, Poznan, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Zaorska
authors.affiliation: Department of Pathophysiology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Sosińska
authors.affiliation: Department of Nursing, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Klejewski
authors.affiliation: Division of Infertility and Reproductive Endocrinology, Department of Gynecology, Obstetrics and Gynecological Oncology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Brązert
authors.affiliation: Department of Histology and Embryology, Poznan University of Medical Sciences, Swiecickiego 6 St., 61-781, Poznan, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Nowicki
authors.affiliation: Department of Histology and Embryology, Poznan University of Medical Sciences, Swiecickiego 6 St., 61-781, Poznan, Poland.|Department of Histology and Embryology, Wrocław Medical University, Wroclaw, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Zabel
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D019450:Genes, MDR; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000970:Antineoplastic Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human
keywords: Chemotherapy; Drug resistance; Drug transporters; Ovarian cancer