We report a quantitative structure-activity relationship study of a new class of pyrazole-pyridine copper complexes that establishes a clear correlation between the ability to promote copper accumulation and cytotoxicity. Intracellular metal accumulation is maximized when ligand lipophilicity allows the complex to rapidly cross the membrane. Copper and ligand follow different uptake kinetics and reach different intracellular equilibrium concentrations. These results support a model in which the ligand acts as an ionophore for the metal ion, cycling between intra- and extracellular compartments as dissociated or complexed entities. When treating cancer cells with structurally unrelated disulfiram and pyrazole-pyridine copper complexes, as well as with inorganic copper, the same morphological and molecular changes were reproduced, indicating that copper overload is responsible for the cytotoxic effects. Copper-based treatments drive sensitive cancer cells toward paraptotic cell death, a process hallmarked by endoplasmic reticulum stress and massive vacuolization in the absence of apoptotic features. A lack of caspase activation, as observed in copper-treated dying cells, is a consequence of metal-mediated inhibition of caspase-3. Thus, copper acts simultaneously as an endoplasmic reticulum (ER) stress inducer and a caspase-3 inhibitor, forcing the cell into caspase-independent paraptotic death. The establishment of a mechanism of action common to different copper binding agents provides a rationale for the exploitation of copper toxicity as an anticancer tool.
This study reports the structure-activity relationship of a series of 8-hydroxoquinoline derivatives (8-HQs) and focuses on the cytotoxic activity of 5-Cl-7-I-8-HQ (clioquinol, CQ) copper complex (Cu(CQ)). 8-HQs alone cause a dose-dependent loss of viability of the human tumor HeLa and PC3 cells, but the coadministration of copper increases the ligands effects, with extensive cell death occurring in both cell lines. Cytotoxic doses of Cu(CQ) promote intracellular copper accumulation and massive endoplasmic reticulum vacuolization that precede a nonapoptotic (paraptotic) cell death. The cytotoxic effect of Cu(CQ) is reproduced in normal human endothelial cells (HUVEC) at concentrations double those effective in tumor cells, pointing to a potential therapeutic window for Cu(CQ). Finally, the results show that the paraptotic cell death induced by Cu(CQ) does not require nor involve caspases, giving an indication for the current clinical assessment of clioquinol as an antineoplastic agent.
The El Tatio geothermal field is located at an height of 4200-4300 m on the Cordillera de los Andes (Altiplano). Geysers, hot pools and mudpots in the geothermal field and local meteoric waters were sampled in April 2002 and analyzed for major and trace elements, delta(2)H, delta(18)O and H-3 of water, delta(34)S and delta(18)O of dissolved sulfate, delta(13)C of dissolved total carbonate, and Sr-87/Sr-86 ratio of aqueous strontium. There are two different types of thermal springs throughout the field, that are chloride-rich water and sulfate-rich water. The chemical composition of chloride springs is controlled by magma degassing and by water-rock interaction processes. Sulfate springs are fed by shallow meteoric water heated by ascending gases. In keeping with the geodynamic setting and nature of the reservoir rocks, chloride water is rich in As, B, Cs, Li; on the other hand, sulfate water is enriched only in B relative to local meteoric water. Alternatively to a merely meteoric model, chloride waters can be interpreted as admixtures of meteoric and magmatic (circa andesitic) water, which moderately exchanges oxygen isotopes with rocks at a chemical Na/K temperature of about 270 degrees C in the main reservoir, and then undergoes loss of vapor (and eventually mixing with shallow water) and related isotopic effects during ascent to the surface. These chloride waters do not present tritium and can be classified as submodern (pre-1952). A chloride content of 5,400 mg/l is estimated in the main reservoir, for which delta(2)H and delta(18)O values, respectively of -78 parts per thousand and -6.9 parts per thousand, are calculated applying the multistage-steam separation isotopic effects between liquid and vapor. From these data, the meteoric recharge (Cl approximate to 0 mg/l) of the main reservoir should approach a composition of 107 parts per thousand in delta(2)H and -14.6 parts per thousand in delta(18)O, when a magmatic water of delta(2)H = -20 parts per thousand, delta(18)O = +10 parts per thousand and Cl = 17,500 mg/l is assumed. The Sr-87/Sr-86 ratios of the hot springs are quite uniform (0.70876 to 0.70896), with values within the range observed for dacites of the Andean central volcanic zone. A water delta(18)O-Sr-87/Sr-86 model was developed for the main geothermal reservoir, by which a meteoric-magmatic composition of the fluids is not excluded. The uniform delta(34)S (SO42-) values of +1.4 to +2.6 parts per thousand, in the chloride waters agree with a major deep-seated source for sulfur, possibly via hydrolysis in the geothermal reservoir of sulfur dioxide provided by magma degassing, followed by isotopic exchange between sulfate and sulfide in the main reservoir. This interpretation is supported by the largely negative delta(34)S (SO42-) value in steam-heated water sulfate (-9.8 parts per thousand) and mass-balance calculation, which exclude leaching at depth of igneous iron-sulfides with delta(34)S near zero per mill. All the delta(13)C values of total carbonate in the chloride waters are negative, w...
The salt waters from the Emilia-Romagna sector of the Northern Apennine Foredeep have been investigated using major and trace element and stable isotope (d 2 H, d 18 O, d 37 Cl, d 81 Br and 87 Sr/ 86 Sr ratio). Ca, Mg, Na, K, Sr, Li, B, I, Br and SO 4 vs. Cl diagrams suggest the subaerial evaporation of seawater beyond gypsum and before halite precipitation as primary process to explain the brine's salinity, whereas saline to brackish waters were formed by mixing of evaporated seawater and water of meteoric origin. A diagenetic end-member may be a third component for mud volcanoes and some brackish waters. Salinization by dissolution of (Triassic) evaporites has been detected only in samples from the Tuscan side of the Apennines and/or interacting with the Tuscan Nappe. In comparison with the seawater evaporation path, Ca-Sr enrichment and Na-K-Mg depletion of the foredeep waters reveal the presence of secondary processes such as dolomitization-chloritization, zeolitization-albitization and illitization. Sulfate concentration, formerly buffered by gypsum-anhydrite deposition, is heavily lowered by bacterial and locally by thermochemical reduction during burial diagenesis. From an isotopic point of view, data of the water molecule confirm mixing between seawater and meteoric endmembers. Local 18 O-shift up to ?11% at Salsomaggiore is related to water-rock interaction at high temperature (&150°C) as confirmed by chemical (Mg, Li, Ca distribution) and isotopic (SO 4 -H 2 O) geothermometers. 37 Cl/ 35 Cl and 81 Br/ 79 Br ratios corroborate the Electronic supplementary material The online version of this article (marine origin of the brines and evidence the diffusion of halogens from the deepest and most saline aquifers toward the surface. The 87 Sr/ 86 Sr ratio suggests a Miocene origin of Sr and rule out the hypothesis of a Triassic provenance of the dissolved components for the analyzed waters issuing from the Emilia-Romagna sector of the foredeep. Waters issuing from the Tuscan side of the Apennines and from the Marche sector of the foredeep show higher 87 Sr/ 86 Sr ratios because of the interaction with siliciclastic rocks.
The thioamido function of [CuCl2(1H)]Cl (2) (1=4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole), a cytotoxic copper complex, was converted into thioether moieties, leading to the synthesis of [CuCl2(3)]2 (4) and [CuCl2(5)] (6) (3=6-methyl-3-pyridin-2-yl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine; 5=4-amino-5-ethylthio-3-(2-pyridyl)-1,2,4-triazole). These complexes were structurally characterized, and their stability constants, along with their biological activity, were determined. 4 and 6 were slightly less stable and significantly less active than 2. However, as 2, both complexes induced nonapoptotic vacuolar cell death. Copper uptake, investigated in both 2-sensitive and -insensitive cell types, was markedly higher in sensitive cells where it was associated with an increase in oxidized glutathione. These data suggest that the thioamido function enhances the cytotoxicity of copper complexes in cancer cells promoting the accumulation of the metal and its interaction with cell thiols.
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