title: Arene-Ru(II) complexes of curcumin exert antitumor activity via proteasome inhibition and apoptosis induction.
abstract: Organometallic ruthenium(II) complexes of general formula [(η(6)-arene)Ru(curcuminato)Cl], with arene being p-iPrC6 H4Me (1), C6H6 (2), and C6Me6 (3), were synthesized, characterized, and evaluated for their antitumor effects. Specifically, we explored their ability to regulate the proteasome, a validated pharmacological target in cancer treatment. Ruthenium complexes inhibited isolated proteasomes to various extents, with the biological activity of these complexes depending on the nature of the bound arene; in particular, [(η(6)-arene)Ru(curcuminato)Cl] 2 suppressed proteasomal activities more potently than 1, 3, or free curcumin. Each complex also inhibited proteasomes in cultured colon cancer cells and consequently triggered apoptosis, with the [(η(6)-benzene)Ru(curcuminato)Cl] complex 2 being the most active. The influence on the oxidative status of HCT116 cells and the DNA binding ability of the [(η(6)-arene)Ru(curcuminato)Cl] complexes were studied. Complex 2 showed the highest antioxidant capacity; moreover, complexes 1 and 2 were shown to bind isolated DNA with higher affinity (up to threefold) than free curcumin. Collectively, our results demonstrate that the complexation of curcumin with ruthenium(II) is a promising starting point for the development of curcumin-based anticancer drugs.
authors.affiliation: School of Biosciences and Biotechnology, University of Camerino via Gentile III da Varano, 62032 Camerino (MC) (Italy). laura.bonfili@unicam.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Bonfili
authors.forename: Riccardo
authors.initials: R
authors.lastname: Pettinari
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cuccioloni
authors.forename: Valentina
authors.initials: V
authors.lastname: Cecarini
authors.forename: Matteo
authors.initials: M
authors.lastname: Mozzicafreddo
authors.forename: Mauro
authors.initials: M
authors.lastname: Angeletti
authors.forename: Giulio
authors.initials: G
authors.lastname: Lupidi
authors.forename: Fabio
authors.initials: F
authors.lastname: Marchetti
authors.forename: Claudio
authors.initials: C
authors.lastname: Pettinari
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Eleuteri
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003474:Curcumin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D061988:Proteasome Inhibitors; D012428:Ruthenium; D004247:DNA; D046988:Proteasome Endopeptidase Complex; D003474:Curcumin