Anti-metastatic and Anti-angiogenic Properties of Potential New Anti-cancer Drugs Based on Metal Complexes of Selenosemicarbazones

Manja      Zec; Tatjana      Srdic-Rajic; Aleksandra      Konic-Ristic; Tamara      Todorovic; Katarina      Andjelkovic; Ivana      Filipovic-Ljeskovic; Sinisa      Radulovic

Abstract

Our previous studies showed that zinc (II), cadmium (II) and nickel (II) complexes with 2-formylpyridine selenosemicarbazone induce apoptosis in cancer cells via activation of mitochondrial pathway. Herein, we reported their antimetastatic properties. Nickel (II), and zinc (II) complexes exhibited the strongest inhibitory potential towards MMP-2/9, while all investigated compounds significantly decreased proteolytic activity of MMP-2/9 in human breast cancer MDA-MB-361 cells. As shown by in vitro transmembrane assays, nickel (II) complex was the most effective in inhibiting invasion of MDA-MB-361 cells, while the cadmium (II) complex was the most active in inhibiting HeLa cells invasion. In malignant cells, the complexes inhibited intracellular accumulation of reactive oxygen species, known for its pro-angiogenic properties via VEGF signaling, but no reduction in total cellular amount of VEGF was found. Furthermore, tubulogenesis test showed anti-angiogenic effect of the complexes in treated endothelial cells. Data indicate multiple mechanisms of the complexes’ anti-angiogenic properties. In addition, they could modulate metastatic phenotype of tumor cells. Nickel (II) complex with 2-formylpyridine selenosemicarbazone revealed to be the most potent.

Keywords: Antiangiogenic potential, Antiinvasive potential, Antimetastatic potential, Cadmium, Cisplatin, Matrix-metalloproteinase, Metal complexes, Metastasis, Nickel, Oncology, Reactive oxygen species, Selenosemicarbazones, Tubulogenesis, VEGF, Zinc