New metalo-therapeutics of NSAIDs against human breast cancer cells

Abstract

The non steroidal anti-inflammatory drugs (NSAID's)-silver(I) metallodrugs of aspirin (aspH), salicylic acid (salH₂), naproxen (napH) acid or p-hydrobenzoic acid (pHbzaH) and the mitochondriotropic triphenylarsine (tpAs) with the formulae [Ag(asp)(tpAs)₃] (1), [Ag(salH)(tpAs)₃] (2), [Ag(nap)(tpAs)₃] (3) and {[Ag(pHbza)(tpAs)₃]∙(dmf)} (4) and [Ag(tpAs)₃(NO₃)] (5) have been synthesized and characterized by m.p., FT-IR, UV-vis and ¹H NMR, spectroscopic techniques and X-ray crystallography. The in vitro cytotoxic activity of 1-5 against human breast adenocarcinoma cancer cells: MCF-7 (positive to estrogen receptors (ERs)) and MDA-MB-231 (negative to estrogen receptors (ERs)) was evaluated. Compound 4 exhibits the stronger activity against MCF-7 (2.5 ± 0.1 μΜ), while 1 the strongest one against MDA-MB-231 (3.2 ± 0.3 μΜ). The IC₅₀ values against normal human fetal lung fibroblast cells lie between 3.0 and 3.7 μΜ. The toxic effect of 1-5 was evaluated against normal human fetal lung fibroblast cells (MRC-5 cells). The IC₅₀ values of 1-5 lie between 2.9 and 3.7 μΜ. The genotoxicity or not of 1-5 against MRC-5 cells was detected from the presence or absence of micronucleus using fluorescence microscopy. The presence of micronucleus in MRC-5 cells (3.0-3.7% in contrast to 1% of the untreated cells) confirms the in vitro toxic behaviour of the compounds. The apoptotic pathway, though the mitochondrion, was confirmed by cell cycle arrest (increasing of the apoptotic cells, in sub-G₁ phase (3.5 (5) - 13.3% (4)) in contrast of 1.8% in the control group) and permeabilization of the mitochondrial membrane test (MMP assay). Moreover, the ability of 1-5 to interact with Calf Thymus (CT)-DNA was also studied. Compound 4 exhibits the highest DNA binding constant (K_b= (25.0 ± 9.7) × 10⁴ M^-1). The inhibitory activity of 1-5 against the enzyme lipoxygenase (LOX) is also investigated. The activity order is 1 > 4 > 3 > 2,5.

Keywords: Biological inorganic chemistry; Cytotoxicity; Drugs design; NSAIDs; Silver(I).