The (iso-)flavonoids chrysin 1, apigenin 2, genistein 3 and their homoleptic copper(II) complexes 4-6 were compared for general cancer cell growth inhibition and for antimetastatic effects on rapidly proliferating and metastasizing 518A2 melanoma cells. The complexes 4-6 were three to five times more active than the free flavonoids in cytotoxicity assays with MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] against 518A2 melanoma, HCT-116 colon, KB-V1/Vbl cervix, and MCF-7/Topo breast carcinoma cells. This activity correlated with an arrest of the cell cycle of 518A2 melanoma cells at the G2/M transition. The complexes also diminished the migration propensity of these cells in wound healing assays more distinctly than the flavonoid ligands. By fluorescent staining of F-actin and beta-catenin the antimetastatic effects of the Cu(II) genistein complex 6 were shown to originate from a remodeling of the actin cytoskeleton and an increase in cadherin-catenin complex formation, factors that favor cell-cell adhesion. Complex 6 also attenuated the expression and secretion of the metastasis-relevant matrix metalloproteinases MMP-2 and MMP-9. In summary, coordination of apigenin and genistein to Cu(II) greatly enhances the antitumoral properties of these flavonoids and potentiates their mechanistic diversity.
Keywords: Actin; Antimetastatic drugs; Beta-catenin; Copper chelate complexes; Flavonoids; Matrix metalloproteinases.
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