Mechanistic studies of in vitro anti-proliferative and anti-inflammatory activities of Zn(II)-NSAID complexes of 1,10-phenanthroline-5,6-dione in MDA-MB-231 cells

Two zinc(II)-NSAID complexes [(phendione)ZnII(NPR)2(H2O)2] (1) and [(phendione)ZnII(MFN)2] (2) (HNPR = naproxen and HMFN = mefenamic acid) of 1,10-phenanthroline-5,6-dione (phendione) were isolated and characterized to evaluate their potential as anti-cancer agents. Each of the complexes contains two equivalents of NSAID per zinc(II)-phendione unit. The complexes are stable in solution under cell culture conditions. Cytotoxic assay on human breast cancer cell line (MDA-MB-231) reveals that the anti-proliferative activity of phendione is retained in both the complexes. The anti-inflammatory properties of NSAIDs are also preserved in the metal complexes as evident from the PGE2 assay. Both 1 and 2 exhibit selective COX-1 inhibition at a low concentration. Furthermore, the zinc(II)-naproxen complex (1) disrupts the intercellular bridges displaying in vitro delay in cellular migration and down regulation of EMT-related genes. The mechanistic studies indicate that the ternary complexes are more active compared to cisplatin and have potential to overcome cisplatin resistance in MDA MB 231 cells. These findings demonstrate that the zinc(II)-NSAID complexes are worthy of further in vivo studies for their promising anti-tumor potential.