Viability and oxidative response of human colorectal HCT-116 cancer and human lung healthy pleura MRC-5 cell lines treated with novel bridged heteronuclear Zn(II)-L-Cu(II)

Abstract

Design of novel non-platinum DNA and protein targeting metal-based anticancer agents have gained importance in recent year. They could be alternatives to platinum-based drugs due to their better characteristics and less negative side effects. Zinc and copper ions play important role in many enzymatic reactions and their antagonist property is essential for biological functions. One of the important zinc and copper enzyme, superoxide dismutase (SOD) keeps the cell safe from the metabolic wastes. Bridged heteronuclear Zn(II)-L-Cu(II) complexes could have improved cytotoxic activity and induce better oxidative response of cancer cells. The novel heteronuclear complexes [{ZnCl(terpy)(μ-pyrazine)CuCl(terpy)}](ClO4)2 (Zn-L1-Cu) and [{ZnCl(terpy)(μ-4,4′-bipyridyl)CuCl(terpy)}](ClO4)2 (Zn-L2-Cu) (where terpy = 2,2′:6′,2′′-terpyridine, L1 = pyrazine, L2 = 4,4′-bipyridyl) were synthesized. The cytotoxic activity of heteronuclear Zn-L1-Cu and Zn-L2-Cu complexes was determined on human colorectal (HCT-116) and human lung healthy pleura (MRC-5) cancer cell lines. Both complexes significantly reduced cell viability on tested cell lines and exerted significant cytotoxic effects, with better effect on HCT-116 cells than cisplatin, especially after 72 h (IC50 < 0.01mM). Selective-index (SI) was calculated by comparing pure compound IC50 values in MRC-5 cell line against the IC50 of the same compound in cancer cell lines. Results of investigated redox parameters indicated significant increase in superoxide anion radical and nitrites in treated cells. Complexes induced significant increase in reactive radical species which consequently induced cell death and thus lower IC50 values. As the response of the cells to an increased radical level induced by treatment, glutathione level also increased in a time and dose dependent manner.