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The Bulk Osteosarcoma and Osteosarcoma Stem Cell Activity of a Necroptosis-Inducing Nickel(II)-Phenanthroline Complex
Arvin Eskandari1, Marie Flamme2, Zhiyin Xiao3
1School of Pharmacy, University College London, London, WC1N 1AX, UK.
Abstract:
We 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.
Insights
A novel nickel(II) complex shows potent anti-osteosarcoma and anti-osteosarcoma stem cell activity. This complex induces cell death via a distinct necroptosis pathway, offering a promising new avenue for osteosarcoma treatment.
Area of Science:
- Inorganic Chemistry
- Cancer Biology
- Pharmacology
Background:
- Osteosarcoma is a primary bone malignancy with limited treatment options.
- Osteosarcoma stem cells (OSCs) contribute to tumor recurrence and metastasis.
- Developing novel therapeutic agents targeting both bulk tumor cells and OSCs is crucial.
Purpose of the Study:
- To investigate the anti-osteosarcoma and anti-OSC properties of a novel nickel(II) complex.
- To elucidate the mechanism of cell death induced by the nickel(II) complex.
- To compare the efficacy of the nickel(II) complex with existing platinum-based chemotherapy drugs.
Main Methods:
- Synthesis and characterization of the nickel(II) complex (Complex 1).
- In vitro evaluation of Complex 1's cytotoxicity against osteosarcoma cell lines and OSCs in 2D and 3D cultures.
- Mechanistic studies involving cell death assays (necroptosis markers), mitochondrial membrane potential assessment, and propidium iodide uptake.
- Analysis of reactive oxygen species (ROS) levels and poly (ADP-ribose) polymerase 1 (PARP-1) activity.
Main Results:
- Complex 1 demonstrated significant anti-osteosarcoma and anti-OSC activity in the micromolar range.
- Complex 1 exhibited comparable or superior potency against OSCs compared to cisplatin and carboplatin.
- Mechanistic studies revealed that Complex 1 induces necroptosis, characterized by necrosome-dependent mitochondrial depolarization and propidium iodide uptake.
- The necroptosis induced by Complex 1 is distinct from known inducers as it does not involve elevated ROS or PARP-1 activity.
Conclusions:
- The nickel(II) complex, 1, possesses significant potential as an anti-osteosarcoma and anti-OSC agent.
- Complex 1 induces cell death through a novel necroptosis pathway, distinct from established mechanisms.
- This study represents the first report on the anti-cancer properties of a nickel complex against osteosarcoma and its stem cells.
