Cytotoxicity of Cu(II) and Zn(II) 2,2′-Bipyridyl Complexes: Dependence of IC₅₀ on Recovery Time

Abstract

We measure the cytotoxicity of three metal complexes containing the 2,2'-bypyridine ligand, Cu(bpy)(NCS)(2), 1, [Cu(bpy)(2)(H(2)O)](PF(6))(2), 2, and Zn(bpy)(2)(NCS)(2), 3, toward neuroblastoma cells (SK-N-SH) and ovarian cancer cells (OVCAR-3) using two different cell assays. The cells were exposed to various concentrations of the compounds for 1 h and the percent inhibition of cell growth, I, measured for various times after exposure, i.e., as a function of the recovery time t. After developing the theory showing the relationship between I and t, the cytotoxicity data were analyzed to reveal that the two copper complexes, 1 and 2, cause the cells to divide at a slower rate than the controls during the recovery period, but the zinc complex, 3, had little or no effect on cell division during the recovery period. The usual metric for reporting cytotoxicity is IC(50), which is the concentration of agent required to inhibit cell growth to 50% of the control population. However, since IC(50) can depend on the recovery time, t, as is the case for 1 and 2, reporting IC(50) for a single recovery time can hide important information about the long-time effects of a cytotoxic agent on the health of the cell population. Mechanistic studies with the compounds revealed that the copper complexes, 1 and 2, cleave closed circular pBR322 DNA in the presence of ascorbate, while the zinc complex, 3, does not facilitate DNA cleavage under the same conditions. This difference in DNA cleavage activity may be related to the fact that Cu(II) is redox active and can readily change its oxidation state, while Zn(II) is redox inert and cannot participate in a redox cycle with ascorbate to break DNA.

How Consistent are Publicly Reported Cytotoxicity Data? Large‐Scale Statistical Analysis of the Concordance of Public Independent Cytotoxicity Measurements

“…Moreover, short‐term assays might overestimate compound activity as cells might recover after some time . These highlights the importance of specifying the incubation time in the presence of the test compounds.…”

“…Moreover,s hort-term assays might overestimate compound activity as cells might recover after some time. [64] These highlights the importance of specifying the incubation time in the presence of the test compounds. This is even more crucial when using assays that allow fors ubstantial variation in incubation times,f or example, incubation time with test compounds in the MTT assay might vary between 24 and 72 h. Several studies have already highlighted the variability across metabolic assays, and between these and assays not based on cell metabolic activity.…”

“…ChemMedChem 2016, 11,[57][58][59][60][61][62][63][64][65][66][67][68][69][70][71] www.chemmedchem.org the s E value estimated from the entire curated data set, namely 1.00 pIC 50 units. However,t his s E value is comparable to that obtainedf or the set of measurement pairs displaying a DpIC 50 value lower than 2.5, namely 0.76 pIC 50 units.…”

Synthesis, structures, nuclease activity, cytotoxicity, DFT and molecular docking studies of two nitrato bridged homodinuclear (Cu-Cu, Zn-Zn) complexes containing 2,2′-bipyridine and a chalcone derivative

“…On the other hand, nitrate represents very common bridging ligand acting through diff erent coordination modes [19] yet structural and biological studies of metal complexes bridged by nitrate are scarce. Thus, based on such precedence, and in view of remarkable DNA binding, cleavage and cytotoxicity [20,21] exhibited by copper bipyridine complexes planar aromatic organics species such as 2,2′ bipyridine was selected as a ligand. The selectivity of a hydroxyl chalcone embedded with a conjugated anthracenyl fra-meworks as ligand was also considered important owing to its phar-maceutical importance [22] and ability to act as bidentate O,O' donor which may probably involve in the construction of H-bonded networks in view of our earlier report [23,24].…”

Nitric oxide- and cisplatin-releasing silica nanoparticles for use against non-small cell lung cancer

“…The percent (%) survival data was fit to an exponential regression using Microsoft Excel Solver, and IC 50 values determined [42].…”