title: Induction of resistance to Aplidin in a human ovarian cancer cell line related to MDR expression.
abstract: Aplidin-resistant IGROV-1/APL cells were derived from the human ovarian cancer IGROV-1 cell line by exposing the cells to increasing concentration of Aplidin for eight months, starting from a concentration of 10 nM to a final concentration of 4 microM. IGROV-1/APL cell line possesses five fold relative resistance to Aplidin. IGROV-1/APL resistant cell line shows the typical MDR phenotype: (1) increased expression of membrane-associated P-glycoprotein, (2) cross-resistance to drugs like etoposide, doxorubicin, vinblastine, vincristine, taxol, colchicin and the novel anticancer drug Yondelis (ET-743). The Pgp inhibitor cyclosporin-A restored the sensitivity of IGROV-1/APL cells to Aplidin by increasing the drug intracellular concentration. The resistance to Aplidin was not due to the other proteins, such as LPR-1 and MRP-1, being expressed at the same level in resistant and parental cell line. The finding that cells over-expressing Pgp are resistant to Aplidin was confirmed in CEM/VLB 100 cells, that was found to be 5-fold resistant to Aplidin compared to the CEM parental cell line.
authors.affiliation: Department of Oncology, Flow Cytometry Unit, Mario Negri Institute, Milan, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tognon
authors.forename: Sergio
authors.initials: S
authors.lastname: Bernasconi
authors.forename: Nicola
authors.initials: N
authors.lastname: Celli
authors.forename: Glynn T
authors.initials: GT
authors.lastname: Faircloth
authors.forename: Carmen
authors.initials: C
authors.lastname: Cuevas
authors.forename: José
authors.initials: J
authors.lastname: Jimeno
authors.forename: Eugenio
authors.initials: E
authors.lastname: Erba
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D047630:Depsipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019450:Genes, MDR; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D010456:Peptides, Cyclic / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D010456:Peptides, Cyclic; D016572:Cyclosporine; C098980:plitidepsin