title: Complex forming competition and in-vitro toxicity studies on the applicability of di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT) as a metal chelator.
abstract: Di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT) is a potential candidate in chelation therapy as an iron chelator. This study showed that a combined treatment with 2μM easily available Fe(II), Cu(II) and Zn(II) each and 5μM Dp44mT on eight different cancer cell lines resulted in a 10-40-fold increase in the intracellular Cu content compared to control samples. The uptake of Cu and Cu-dependent cytotoxicity strictly depend on the Cu concentration of the culture medium. Even as low concentration of Dp44mT as 0.1μM can transport high amounts of copper inside the cells. The Cu accumulation and toxicity through Dp44mT can hardly be influenced by Fe. Copper uptake and toxicity triggered by 2μM extracellular Cu(II) and 5μM Dp44mT could not be influenced by Fe(II) extracellular concentrations even 50-times higher than that of Cu(II). A 50-times higher Co(II) extracellular concentration hindered the Cu(II) uptake almost completely and a 10-times higher Co(II) concentration already decreased the Dp44mT-mediated Cu toxicity. Conditional complex stability constant determinations for Dp44mT with Cu(II), Co(II), Fe(II), Ni(II) and Zn(II) revealed that the metal-to-ligand ratio is 1:1 in [Cu(II)Dp44mT] complex, while for Co(II), Fe(II) and Ni(II) is 1:2. The highest stability constant was obtained for Cu(II) (lg β=7.08±0.05) and Co(II) (lg β2=12.47±0.07). According to our results, Dp44mT in combination with Cu is highly toxic in vitro. Therefore, the use of Dp44mT as an iron chelator is limited if biologically available Cu is also present even at low concentrations.
authors.affiliation: Laboratory of Environmental Chemistry and Bioanalytics, Department of Analytical Chemistry, Institute of Chemistry, Eötvös Loránd University, Budapest, Hungary.
authors.forename: Anikó
authors.initials: A
authors.lastname: Gaál
authors.forename: Gábor
authors.initials: G
authors.lastname: Orgován
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Polgári
authors.forename: Andrea
authors.initials: A
authors.lastname: Réti
authors.forename: Victor G
authors.initials: VG
authors.lastname: Mihucz
authors.forename: Szilvia
authors.initials: S
authors.lastname: Bősze
authors.forename: Norbert
authors.initials: N
authors.lastname: Szoboszlai
authors.forename: Christina
authors.initials: C
authors.lastname: Streli
mesh_terms: D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry* / Q000633:toxicity*; D003035:Cobalt / Q000737:chemistry / Q000378:metabolism; D003300:Copper / Q000378:metabolism / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry / Q000633:toxicity; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D011522:Protons; D013882:Thiosemicarbazones / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D015032:Zinc / Q000737:chemistry / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D007502:Iron Chelating Agents; D011522:Protons; D013882:Thiosemicarbazones; C539263:di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone; D003035:Cobalt; D003300:Copper; D007501:Iron; D015032:Zinc
keywords: Cancer therapy; Cobalt; Copper poisoning; Iron chelator; Metal transport; TXRF