title: Contrasting cellular uptake pathways for chlorido and iodido iminopyridine ruthenium arene anticancer complexes.
abstract: The pathways involved in cellular uptake and accumulation of iminopyridine complexes of general formula [Ru(η(6)-p-cymene)(N,N-dimethyl-N'-[(E)-pyridine-2-ylmethylidene]benzene-1,4-diamine)X]PF(6) bearing two different halido ligands X = Cl or I, have been explored. The ratio of passive/active cellular accumulation of Ru in A2780 human ovarian cancer cells is compared and contrasted with cisplatin. Also, saturation of cellular uptake, time-dependence of cellular influx/efflux equilibria, together with endocytotic pathways such as caveolae and facilitated diffusion are investigated and discussed. Temperature dependence studies of Ru accumulation in the A2780 cells show that in contrast to cisplatin (CDDP) and chlorido complex , which are taken up largely through active transport, the iodido complex enters cells via passive transport. The cellular efflux of Ru is slow (ca. 25% retained after 72 h) and is partially inhibited by verapamil, implicating the P-gp protein in the efflux mechanism. Ouabain inhibition experiments suggest that the cellular uptake of these ruthenium complexes relies at least in part on facilitated diffusion, and in particular is dependent on the membrane potential. In addition the finding that depletion of cellular ATP with antimycin A had little effect on cellular Ru accumulation from iodido complex is consistent with passive diffusion. In contrast, ATP depletion caused a major increase in cellular accumulation of ruthenium from chlorido complex .
authors.affiliation: Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Isolda
authors.initials: I
authors.lastname: Romero-Canelón
authors.forename: Ana M
authors.initials: AM
authors.lastname: Pizarro
authors.forename: Abraha
authors.initials: A
authors.lastname: Habtemariam
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001693:Biological Transport, Active; D027682:Cation Transport Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000079923:Copper Transporter 1; D004705:Endocytosis; D005260:Female; D006801:Humans; D007700:Kinetics; D053858:Metabolic Networks and Pathways; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017975:Ruthenium Compounds / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D017975:Ruthenium Compounds; C490079:SLC31A1 protein, human; D000255:Adenosine Triphosphate; D000254:Sodium-Potassium-Exchanging ATPase; D002945:Cisplatin