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Metal transport capabilities of anticancer copper chelators

DOI: 10.1016/j.jtemb.2018.01.011 DOI Help

Authors: Anikó Gaál (Eötvös Loránd University) , Gábor Orgován (Semmelweis University; Hungarian Academy of Sciences) , Victor G. Mihucz (Eötvös Loránd University; Hungarian Satellite Trace Elements Institute to UNESCO) , Ian Pape (Diamond Light Source) , Dieter Ingerle (Atominstitut, Technische Universitaet Wien) , Christina Streli (Atominstitut, Technische Universitaet Wien) , Norbert Szoboszlai (Eötvös Loránd University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Trace Elements In Medicine And Biology , VOL 47 , PAGES 79 - 88

State: Published (Approved)
Published: May 2018
Diamond Proposal Number(s): 10230 , 15180

Abstract: In the present study, several Cu chelators [2,2′-biquinoline, 8-hydroxiquinoline (oxine), ammonium pyrrolidinedithiocarbamate (APDTC), Dp44mT, dithizone, neocuproine] were used to study Cu uptake, depletion and localization in different cancer cell lines. To better understand the concentration dependent fluctuations in the Cu intracellular metal content and Cu-dependent in vitro antiproliferative data, the conditional stability constants of the Cu complex species of the investigated ligands were calculated. Each investigated chelator increased the intracellular Cu content on HT-29 cells causing Cu accumulation depending on the amount of the free Cu(II). Copper accumulation was 159 times higher for Dp44mT compared to the control. Investigating a number of other transition metals, intracellular accumulation of Cd was observed only for two chelators. Intracellular Zn content slightly decreased (cca. 10%) for MCF-7 cells, while a dramatic decrease was observed on MDA-MB-231 ones (cca. 50%). A similar decrease was observed for HCT-116, while Zn depletion for HT-29 corresponded to cca. 20%. The IC50 values were registered for the investigated four cell lines at increasing external Cu(II) concentration, namely, MDA-MB-231 cells had the lowest IC50 values for Dp44mT ranging between 7 and 35 nM. Thus, Zn depletion could be associated with lower IC50 values. Copper depletion was observed for all ligands being less pronounced for Dp44mT and neocuproine. Copper localization and its colocalization with Zn were determined by μ-XRF imaging. Loose correlation (0.57) was observed for the MCF-7 cells independently of the applied chelator. Similarly, a weak correlation (0.47) was observed for HT-29 cells treated with Cu(II) and oxine. Colocalization of Cu and Zn in the nucleus of HT-29 cells was observed for Dp44mT (correlation coefficient of 0.85).

Journal Keywords: Copper poisoning; Copper uptake; TXRF; Metal transport

Subject Areas: Biology and Bio-materials, Medicine

Instruments: B16-Test Beamline