title: Dinuclear platinum anticancer complexes with fluorescent N,N'-bis(aminoalkyl)-1,4-diaminoanthraquinones: cellular processing in two cisplatin-resistant cell lines reflects the differences in their resistance profiles.
abstract: The biological activity of N,N'-bis(aminoalkyl)-1,4-diaminoanthraquinones (aminoalkyl is 2-aminoethyl, 3-aminoprop-1-yl and 4-aminobut-1-yl) and their dinuclear platinum complexes has been evaluated in the U2-OS human osteosarcoma cell line and its cisplatin-resistant U2-OS/Pt subline. All the compounds have been found to exhibit high cytotoxicity in the sensitive cell line, and to overcome cisplatin resistance in U2-OS/Pt cells. Cellular processing of N,N'-bis(2-aminoethyl)-1,4-diaminoanthraquinone and the respective dinuclear platinum complex in the sensitive and resistant U2-OS cells has been studied over time using digital fluorescence microscopy. Cellular processing of the compounds has been found to be similar in sensitive and resistant U2-OS cells, which is in agreement with the lack of cross-resistance in the U2-OS/Pt cell line. Both the platinum complex and the free ligand quickly enter the cell and accumulate in the nucleus. The platinum complex is excreted from the cell via the Golgi apparatus, while the weakly basic anthraquinone ligand accumulates in the Golgi complex, where it is taken up by lysosomes and then transported to the cell surface. The cellular distribution of the fluorescent anthraquinones and their dinuclear platinum complexes in the sensitive/resistant pair of U2-OS osteosarcoma cell lines is compared with the earlier studied cellular processing in the sensitive/resistant pair of A2780 ovarian carcinoma cell lines. In the A2780cisR cell line, the platinum complexes (and not the free ligands) are sequestered in lysosomes, which is not the case in A2780 sensitive cells. The differences in cellular distribution of the compounds in these two sensitive/resistant pairs of cell lines most likely result from different resistance profiles in A2780cisR and U2-OS/Pt cells. Lysosomes of A2780cisR cells are less acidic than lysosomes of A2780 sensitive cells, which is likely to be the cause of a defect in endocytosis. The disruption of normal endocytosis might facilitate sequestration of the platinum complexes in lysosomes, which partly confers the cross-resistance of these complexes with cisplatin in the A2780cisR cell line. In contrast, sequestration in acidic vesicles does not occur in U2-OS/Pt cells that do not exhibit enhanced lysosomal pH and which are likely to have normal endocytosis.
authors.affiliation: Gorlaeus Laboratories, Leiden Institute of Chemistry, 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: 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 / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005456:Fluorescent Dyes; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008024:Ligands; D015394:Molecular Structure; D010984:Platinum / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D008024:Ligands; D010984:Platinum; D002945:Cisplatin