title: Mechanism of cytotoxicity and cellular uptake of lipophilic inert dinuclear polypyridylruthenium(II) complexes.
abstract: The accumulation, uptake mechanism, cytotoxicity, cellular localisation of-and mode of cell death induced by-dinuclear ruthenium(II) complexes ΔΔ/ΛΛ-[{Ru(phen)(2) }(2) {μ-bb(n) }](4+) (Rubb(n)), where phen is 1,10-phenanthroline, bb(n) is bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (n=2, 5, 7, 10, 12 or 16), and the corresponding mononuclear complexes containing the bb(n) ligands, were studied in L1210 murine leukaemia cells. Cytotoxicity increased with linker chain length, and the ΔΔ-Rubb(16) complex displayed the highest cytotoxicity of the series, with an IC(50) value of 5 μM, similar to that of carboplatin in the L1210 murine leukaemia cell line. Confocal microscopy and flow cytometry studies indicated that the complexes accumulate in the mitochondria of L1210 cells, with the magnitude of cellular uptake and accumulation increasing with linking chain length in the bb(n) bridge of the metal complex. ΔΔ-Rubb(16) entered the L1210 cells by passive diffusion (with a minor contribution from protein-mediated active transport), inducing cell death via apoptosis. Additionally, metal-complex uptake in leukaemia cells was approximately 16-times that observed in healthy B cells highlighting that the bb(n) series of complexes may have potential as selective anticancer drugs.
authors.affiliation: School of Physical, Environmental and Mathematical Sciences, University of New South Wales, Australian Defence Force Academy, Canberra, ACT, Australia.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Pisani
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Fromm
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Mulyana
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Clarke
authors.forename: Heinrich
authors.initials: H
authors.lastname: Körner
authors.forename: Kirsten
authors.initials: K
authors.lastname: Heimann
authors.forename: J Grant
authors.initials: JG
authors.lastname: Collins
authors.forename: F Richard
authors.initials: FR
authors.lastname: Keene
mesh_terms: D000255:Adenosine Triphosphate; D000818:Animals; D017209:Apoptosis; D002151:Calorimetry; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry* / Q000633:toxicity; D005434:Flow Cytometry; D051379:Mice; D010618:Phenanthrolines / Q000737:chemistry; D012428:Ruthenium / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D056831:Coordination Complexes; D010618:Phenanthrolines; D012428:Ruthenium; D000255:Adenosine Triphosphate; C025205:1,10-phenanthroline