An Osteosarcoma Stem Cell Potent Nickel(II)-Polypyridyl Complex Containing Flufenamic Acid.

Apoptosis resistance is inherent to stem cell-like populations within tumours and is one of the major reasons for chemotherapy failures in the clinic. Necroptosis is a non-apoptotic mode of programmed cell death that could help bypass apoptosis resistance. Here we report the synthesis, characterisation, biophysical properties, and anti-osteosarcoma stem cell (OSC) properties of a new nickel(II) complex bearing 3,4,7,8-tetramethyl-1,10-phenanthroline and two flufenamic acid moieties, . The nickel(II) complex is stable in both DMSO and cell media. The nickel(II) complex kills bulk osteosarcoma cells and OSCs grown in monolayer cultures and osteospheres grown in three-dimensional cultures within the micromolar range. Remarkably, exhibits higher potency towards osteospheres than the metal-based drugs used in current osteosarcoma treatment regimens, cisplatin and carboplatin, and an established anti-cancer stem cell agent, salinomycin (up to 7.7-fold). Cytotoxicity studies in the presence of prostaglandin E2 suggest that kills OSCs in a cyclooxygenase-2 (COX-2) dependent manner. Furthermore, the potency of towards OSCs decreased significantly upon co-treatment with necrostatin-1 or dabrafenib, well-known necroptosis inhibitors, implying that induces necroptosis in OSCs. To the best of our knowledge, is the first compound to implicate both COX-2 and necroptosis in its mechanism of action in OSCs.