Effects of chrysin, apigenin, genistein and their homoleptic copper(II) complexes on the growth and metastatic potential of cancer cells

Abstract

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.