Exploring the Molecular Mechanisms Underlying the in vitro Anticancer Effects of Multitarget‐Directed Hydrazone Ruthenium(II)–Arene Complexes. (18th November 2019)

• Record Type: Journal Article
• Authors: Cuccioloni, Massimiliano; Bonfili, Laura; Cecarini, Valentina; Nabissi, Massimo; Pettinari, Riccardo; Marchetti, Fabio; Petrelli, Riccardo; Cappellacci, Loredana; Angeletti, Mauro; Eleuteri, Anna Maria
• Is Part Of: ChemMedChem. Volume 15:Number 1(2020)
• Page Start: 105
• Page End: 113
• Publication Date: 2019-11-18
• Subjects: Ruthenium complexes -- Metal-based anticancer drugs -- Mechanisms of action -- Cellular targets.; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201900551
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: The molecular targets and the modes of action behind the cytotoxicity of two structurally established N, O‐ or N, N‐hydrazone ruthenium(II)–arene complexes were explored in human breast adenocarcinoma cells (MCF‐7) and paralleled in non‐cancerous and cisplatin‐resistant counterparts (MCF‐10A and MCF‐7CR respectively). Both complexes, [Ru(hmb)(L1)Cl] (1, L1=4‐((2‐(2, 4‐dinitrophenyl)hydrazono)(phenyl)methyl)‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐olate) and [Ru(cym)(L2)Cl] (2, L2=1‐((3‐methyl‐5‐oxo‐1‐phenyl‐1 H ‐pyrazol‐4(5 H )‐ylidene)(phenyl)methyl)‐2‐(pyridin‐2‐yl)hydrazin‐1‐ide), reversibly interact with moderate‐to‐high affinity with a number of molecular targets in cell‐free assays, namely serum albumin, DNA, the 20S proteasome and hydroxymethylglutaryl‐CoA reductase. Most interestingly, only 2 readily crosses the cell membrane and preserves its binding/modulatory ability toward the targets of interest upon rapid cellular internalization. The resulting action at multiple levels of the cancer cascade is likely the cause for the selective sensitization of tumour cells to p27‐mediated apoptotic death, and for the ability of 2 to overcome the drug resistance problem. Abstract : Multitarget molecule : The mechanism of cytotoxicity toward epithelial breast cancer cells of a hydrazone ruthenium(II)‐arene complex is dissected. The complex readily permeates the cell membrane, and selectively triggers apoptosis by inhibition of the proteasome and 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase, and DNA targeting.