title: Cellular uptake and subcellular distribution of ruthenium-based metallodrugs under clinical investigation versus cisplatin.
abstract: The cellular uptake and subcellular distribution including adduct formation with genomic DNA and uptake into mitochondria of two ruthenium(iii)-based drugs in clinical trials, KP1019 and NAMI-A, and cisplatin, was investigated in cisplatin sensitive and resistant A2780 human ovarian carcinoma cells. These data indicate that reduced metal uptake into mitochondria in combination with increased binding towards low molecular weight components involved in detoxification mechanisms is essential for cisplatin resistance. The ruthenium drugs show distinct differences with respect to cisplatin, especially in the cisplatin resistant cells; in comparison to the sensitive cells, KP1019 exhibits higher cytotoxicity and an only slightly changed metabolism of the drug, whereas NAMI-A treatment results in increased intracellular ruthenium levels and a higher number of ruthenium-DNA adducts. In addition, size exclusion-inductively coupled mass spectrometry indicates that adduct formation with high molecular weight components in the particulate and nuclear fractions is crucial for the therapeutic effect of KP1019 in both cisplatin resistant and sensitive cell lines.
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Groessl
authors.forename: Olivier
authors.initials: O
authors.lastname: Zava
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D013058:Mass Spectrometry / Q000379:methods; D008928:Mitochondria / Q000378:metabolism; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D012428:Ruthenium / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017975:Ruthenium Compounds; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D007191:Indazoles; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); C499292:indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III)); D012428:Ruthenium; D004247:DNA; D002945:Cisplatin; D004121:Dimethyl Sulfoxide