title: Dinuclear platinum complexes with N, N'-bis(aminoalkyl)-1,4-diaminoanthraquinones as linking ligands. Part II. Cellular processing in A2780 cisplatin-resistant human ovarian carcinoma cells: new insights into the mechanism of resistance.
abstract: The cellular processing of three fluorescent N, N'-bis(aminoalkyl)-1,4-diaminoanthraquinones (aminoalkyl=2-aminoethyl, 3-aminoprop-1-yl or 4-aminobut-1-yl) and their dinuclear platinum complexes in A2780 human ovarian carcinoma cells with acquired resistance to cisplatin has been monitored over time by time-lapse fluorescence microscopy. The results were compared with the previously reported observations in the parent A2780 cell line. The cellular distribution pattern for the free ligands is similar in sensitive and resistant cells, whereas significant differences in cellular distribution were observed in the case of the platinum complexes. In the cisplatin-resistant cell line the platinum complexes were found to be sequestrated in acidic vesicles in the cytosol from the very beginning of the incubation. This sequestration was not observed in the case of sensitive cells. Platinum accumulation in vesicles possibly presents a mechanism of resistance to platinum complexes. This mechanism appears to be unrelated to the mechanism of deactivation of platinum compounds by glutathione. Encapsulation of the dinuclear platinum complexes in lysosomal vesicles provides a plausible explanation for the decreased activity of these compounds in the resistant cell line, as compared to the sensitive cell line.
authors.affiliation: Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.
authors.forename: Ganna V
authors.initials: GV
authors.lastname: Kalayda
authors.forename: Bart A J
authors.initials: BA
authors.lastname: Jansen
authors.forename: Chris
authors.initials: C
authors.lastname: Molenaar
authors.forename: Peter
authors.initials: P
authors.lastname: Wielaard
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Tanke
authors.forename: Jan
authors.initials: J
authors.lastname: Reedijk
mesh_terms: D000880:Anthraquinones; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D005456:Fluorescent Dyes; D006801:Humans; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D008024:Ligands; D009944:Organoplatinum Compounds; D002945:Cisplatin