Nimesulide Silver Metallodrugs, Containing the Mitochondriotropic, Triaryl Derivatives of Pnictogen; Anticancer Activity against Human Breast Cancer Cells

Abstract

Novel silver(I) metallo-drugs of the nonsteroidal anti-inflammatory drug nimesulide (nim) and the mitochondriotropic triaryl derivatives of pnictogen ligands (tpE, E = P (tpp, tptp, or totp), As (tpAs), Sb (tpSb)) with the formulas {[Ag(nim) (tpp)2]DMF} (1), [Ag(nim) (tptp)2] (2), [Ag(nim) (totp)] (3), [Ag(nim) (tpAs)2] (4), and [Ag(nim) (tpSb)3] (5) ((tpp = triphenyphosphine, tptp = tri(p-tolyl)phosphine, totp = tri(o-tolyl)phosphine, tpAs = triphenylarsine, tpSb = triphenylantimony, and DMF = dimethylformamide) were synthesized and characterized by melting point, vibrational spectroscopy (mid-Fourier transform IR), (1)H NMR, UV-visible spectroscopic techniques, and X-ray crystallography. The in vitro cytotoxic activity of 1-5 against human breast adenocarcinoma cancer cell lines: MCF-7 (estrogen receptor (ER) positive) and MDA-MB-231 (ER negative) was determined. The genotoxicity on normal human fetal lung fibroblast cells (MRC-5) caused by 1-5 was evaluated by fluorescence microscopy. The absence of micronucleus in MRC-5 cells confirms the in vitro non toxicity behavior of the compounds. Because of the morphology of the cells, an apoptotic pathway was concluded for the cell death. The apoptotic pathway, especially though the mitochondrion damage, was confirmed by DNA fragmentation, cell cycle arrest, and permeabilization of the mitochondrial membrane tests. The molecular mechanism of action of 1-5 was further studied by (i) the binding affinity of 1-5 toward the calf thymus (CT) DNA, (ii) the inhibitory activity of 1-5 against lipoxygenase (an enzyme that oxidizes polyunsaturated fatty acids to leukotrienes or prostaglandins), and (iii) the catalytic activity of 1-5 on the oxidation of linoleic acid (an acid that partakes in membrane fluidity, membrane enzyme activities, etc.) to hyperoxolinoleic acid by oxygen.

Poly Organotin Acetates against DNA with Possible Implementation on Human Breast Cancer

“…In conclusion, 1 and 2 stimulate S-phase cell cycle arrest, thus suppressing cell proliferation by inhibiting DNA synthesis, in accordance to other anticancer agents (resveratrol, mitomycin C, and hydroxyurea) [ 37 ]. Likewise, cisplatin causes cell cycle arrest at S and G 2 /M phases and the percentage of MCF-7 cells in sub-G 1 phase is increased, exhibiting an increasing number of apoptotic cells [ 37 ]. To summarize, metal drugs of this type induce cell cycle arrest either in G 0 /G 1 or in S phase (like cisplatin), resulting in MCF-7 cell growth inhibition.…”

“…Micronucleus assay is a reliable and an accessible technique to evaluate the appearance of genetic damage on a cell. The detection of micronucleus (MN) indicates mutagenic, genotoxic, or teratogenic effects [ 37 ]. In the presence of exogenous genotoxic factors, the MN is formed due to the metaphase–anaphase transition of the mitotic cycle.…”

“…However, the micronucleus frequencies are slightly increased when the cells are incubated with 1 and 2 to 2.10 ± 0.04% ( 1 ) and 2.19 ± 0.03% ( 2 ) ( Figure S3 ). The compounds 1 and 2 show a slightly increase in micronucleus frequency in contrast to the control or to cisplatin (1.6%) at its IC 50 value of 26 μΜ [ 37 ]. Cisplatin is used as a reference control.…”

“…Internucleosomal DNA fragmentation has been described as one of the main characteristics of the apoptotic process and can be identified by a sub-G 1 peak on DNA frequency histograms [ 37 ]. Therefore, the apoptotic type of the cell deaths caused by the regulation of cell cycle progression because of 1 and 2 can be evaluated by flow cytometric analysis since these cells give a sub-G 1 peak [ 37 ]. The percentage of cells in the phases of the cell cycle was analyzed after 48 h exposure of MCF-7 cells with 1 and 2 at their IC 50 values.…”

“…To summarize, metal drugs of this type induce cell cycle arrest either in G 0 /G 1 or in S phase (like cisplatin), resulting in MCF-7 cell growth inhibition. Therefore, the reduced cell growth caused by 1 and 2 is attributed to the apoptotic type of cell death, in accordance to the way of action of cisplatin [ 37 ].…”