Anti-Migratory and Cytotoxic Activities of [Ga(8-hydroxyquinolinato)₃]: Roles of Endogenous Cu(II) and Drug-Induced Phenotypic Changes

As shown by IncuCyte Zoom imaging proliferation assays, invasive triple-negative human breast MDA-MB-231 cancer cells treated with sub-toxic doses (5.0-20 mu M, 72h) of [GaQ(3)] (Q=8-hydroxyquinolinato) caused profound morphological changes and inhibition of cell migration, which were likely due to terminal cell differentiation or similar phenotypical change. This is the first demonstration of potential use of a metal complex in differentiation anti-cancer therapy. Additionally, a trace amount of Cu(II) (0.20 mu M) added to the medium dramatically increased [GaQ(3)] cytotoxicity (IC50 similar to 2 mu M, 72h) due to its partial dissociation and the action of the HQ ligand as a Cu(II) ionophore, as shown with electrospray mass spectrometry and fluorescence spectroscopy assays in the medium. Hence, cytotoxicity of [GaQ(3)] is strongly linked to ligand binding of essential metal ions in the medium, for example, Cu(II). Appropriate delivery mechanisms of such complexes and their ligands could enable a powerful new triple therapeutic approach for cancer chemotherapy, including cytotoxicity against primary tumour, arrest of metastases, and activation of innate and adaptive immune responses.