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

Abstract

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 μM, 72 h) of [GaQ3] (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 μM) added to the medium dramatically increased [GaQ3] cytotoxicity (IC50 ~ 2 μM, 72 h) 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 [GaQ3] is strongly linked to ligand binding of essential metal ions in the medium, e.g., 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.