Copper-Dependent Cytotoxicity of 8‑Hydroxyquinoline Derivatives Correlates with Their Hydrophobicity and Does Not Require Caspase Activation

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.