title: Enhanced complement resistance in drug-selected P-glycoprotein expressing multi-drug-resistant ovarian carcinoma cells.
abstract: Multi-drug resistance (MDR) is a major obstacle in cancer chemotherapy. There are contrasting data on a possible correlation between the level of expression of the drug transporter P-glycoprotein (P-gp) and susceptibility to complement-dependent cytotoxicity (CDC). We therefore investigated the sensitivity of human ovarian carcinoma cells and their P-gp expressing MDR variants to complement. Chemoselected P-gp expressing MDR cells showed increased resistance to CDC associated with overexpression of membrane-bound complement regulatory proteins (mCRP) and increased release of the soluble inhibitors C1 inhibitor and factor I. MDR1 gene transfection alone did not alter the susceptibility of P-gp expressing A2780-MDR and SKOV3-MDR cells to CDC. However, subsequent vincristine treatment conferred an even higher resistance to complement to these cells, again associated with increased expression of mCRP. Blocking the function of P-gp with verapamil, cyclosporine A or the anti-P-gp-antibody MRK16 had no impact on their complement resistance, whereas blocking of mCRP enhanced their susceptibility to complement. These results suggest that enhanced resistance of chemoselected MDR ovarian carcinoma cells to CDC is not conferred by P-gp, but is due at least partly to overexpression of mCRP, probably induced by treatment with the chemotherapeutic agents.
authors.affiliation: Department of Internal Medicine III, Cardiology, University of Freiburg, Freiburg, Germany.
authors.forename: K E
authors.initials: KE
authors.lastname: Odening
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.forename: R
authors.initials: R
authors.lastname: Rutz
authors.forename: S
authors.initials: S
authors.lastname: Laufs
authors.forename: S
authors.initials: S
authors.lastname: Fruehauf
authors.forename: Z
authors.initials: Z
authors.lastname: Fishelson
authors.forename: M
authors.initials: M
authors.lastname: Kirschfink
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D018958:CD55 Antigens / Q000378:metabolism; D018957:CD59 Antigens / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000378:metabolism; D003165:Complement System Proteins / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D018432:Drug Resistance, Multiple / Q000276:immunology; D019008:Drug Resistance, Neoplasm / Q000276:immunology*; D005260:Female; D006801:Humans; D051916:Membrane Cofactor Protein / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C497857:CD46 protein, human; D018958:CD55 Antigens; D018957:CD59 Antigens; D003169:Complement Inactivator Proteins; D051916:Membrane Cofactor Protein; D009363:Neoplasm Proteins; C051590:CD59 protein, human; D003165:Complement System Proteins