title: Copper-dependent cytotoxicity of 8-hydroxyquinoline derivatives correlates with their hydrophobicity and does not require caspase activation.
abstract: This study reports the structure-activity relationship of a series of 8-hydroxoquinoline derivatives (8-HQs) and focuses on the cytotoxic activity of 5-Cl-7-I-8-HQ (clioquinol, CQ) copper complex (Cu(CQ)). 8-HQs alone cause a dose-dependent loss of viability of the human tumor HeLa and PC3 cells, but the coadministration of copper increases the ligands effects, with extensive cell death occurring in both cell lines. Cytotoxic doses of Cu(CQ) promote intracellular copper accumulation and massive endoplasmic reticulum vacuolization that precede a nonapoptotic (paraptotic) cell death. The cytotoxic effect of Cu(CQ) is reproduced in normal human endothelial cells (HUVEC) at concentrations double those effective in tumor cells, pointing to a potential therapeutic window for Cu(CQ). Finally, the results show that the paraptotic cell death induced by Cu(CQ) does not require nor involve caspases, giving an indication for the current clinical assessment of clioquinol as an antineoplastic agent.
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Parma, Viale delle Scienze 17/A, 43123 Parma, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Tardito
authors.forename: Amelia
authors.initials: A
authors.lastname: Barilli
authors.forename: Irene
authors.initials: I
authors.lastname: Bassanetti
authors.forename: Matteo
authors.initials: M
authors.lastname: Tegoni
authors.forename: Ovidio
authors.initials: O
authors.lastname: Bussolati
authors.forename: Renata
authors.initials: R
authors.lastname: Franchi-Gazzola
authors.forename: Claudio
authors.initials: C
authors.lastname: Mucchino
authors.forename: Luciano
authors.initials: L
authors.lastname: Marchiò
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000494:pharmacology*; D004789:Enzyme Activation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D015394:Molecular Structure; D015125:Oxyquinoline / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008024:Ligands; D015125:Oxyquinoline; D003300:Copper; D020169:Caspases