The Bulk Osteosarcoma and Osteosarcoma Stem Cell Activity of a Necroptosis‐Inducing Nickel(II)–Phenanthroline Complex

• DOI: 10.1002/cbic.202000231
• Publication Date: 2020-05-16T14:31:38Z
• Authors: Arvin Eskandari; Marie Flamme; Zhiyin Xiao; Kogularamanan Sun...
• Keywords: Osteosarcoma; 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; Cell Survival; Antineoplastic Agents; Structure-Activity Relationship; 03 medical and health sciences; Coordination Complexes; Nickel; Necroptosis; Neoplastic Stem Cells; Tumor Cells, Cultured; Humans; Drug Screening Assays, Antitumor; Reactive Oxygen Species; Phenanthrolines

AbstractWe report the anti‐osteosarcoma and anti‐osteosarcoma stem cell (OSC) properties of a nickel(II) complex, 1. Complex 1 displays similar potency towards bulk osteosarcoma cells and OSCs, in the micromolar range. Notably, 1 displays similar or better OSC potency than the clinically approved platinum(II) anticancer drugs cisplatin and carboplatin in two‐ and three‐dimensional osteosarcoma cell cultures. Mechanistic studies revealed that 1 induces osteosarcoma cell death by necroptosis, an ordered form of necrosis. The nickel(II) complex, 1 triggers necrosome‐dependent mitrochondrial membrane depolarisation and propidium iodide uptake. Interestingly, 1 does not evoke necroptosis by elevating intracellular reactive oxygen species (ROS) or hyperactivation of poly ADP ribose polymerase (PARP‐1). ROS elevation and PARP‐1 activity are traits that have been observed for established necroptosis inducers such as shikonin, TRAIL and glutamate. Thus the necroptosis pathway evoked by 1 is distinct. To the best of our knowledge, this is the first report into the anti‐osteosarcoma and anti‐OSC properties of a nickel complex.