Related Experiment Video
Updated: Sep 21, 2025
Modeling Osteosarcoma Using Li-Fraumeni Syndrome Patient-derived Induced Pluripotent Stem Cells
Published on: June 13, 2018
An Osteosarcoma Stem Cell Potent Nickel(II)-Polypyridyl Complex Containing Flufenamic Acid
Ginevra Passeri1, Joshua Northcote-Smith1, Roshane Perera1
1School of Chemistry, University of Leicester, Leicester LE1 7RH, UK.
Abstract:
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, 1. The nickel(II) complex 1 is stable in both DMSO and cell media. The nickel(II) complex 1 kills bulk osteosarcoma cells and OSCs grown in monolayer cultures and osteospheres grown in three-dimensional cultures within the micromolar range. Remarkably, 1 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 1 kills OSCs in a cyclooxygenase-2 (COX-2) dependent manner. Furthermore, the potency of 1 towards OSCs decreased significantly upon co-treatment with necrostatin-1 or dabrafenib, well-known necroptosis inhibitors, implying that 1 induces necroptosis in OSCs. To the best of our knowledge, 1 is the first compound to implicate both COX-2 and necroptosis in its mechanism of action in OSCs.
Insights
A novel nickel(II) complex effectively targets and eliminates osteosarcoma stem cells by inducing necroptosis, a programmed cell death pathway. This compound shows promise in overcoming chemotherapy resistance in osteosarcoma treatment.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Drug Discovery
Background:
- Apoptosis resistance in cancer stem cells contributes to chemotherapy failure.
- Necroptosis offers an alternative cell death pathway to bypass apoptosis resistance.
- Osteosarcoma stem cells (OSCs) are crucial for tumor recurrence and metastasis.
Purpose of the Study:
- To synthesize and characterize a novel nickel(II) complex for anti-cancer stem cell activity.
- To evaluate the efficacy of the nickel(II) complex against osteosarcoma stem cells.
- To elucidate the mechanism of action, including the roles of cyclooxygenase-2 (COX-2) and necroptosis.
Main Methods:
- Synthesis and characterization of a nickel(II) complex with phenanthroline and flufenamic acid moieties.
- In vitro assessment of cytotoxicity against osteosarcoma cells and OSCs in 2D and 3D cultures.
- Investigation of the mechanism of action using prostaglandin E2, necrostatin-1, and dabrafenib.
Main Results:
- The nickel(II) complex demonstrated stability in DMSO and cell media.
- The complex exhibited potent cytotoxicity against bulk osteosarcoma cells and OSCs (micromolar range).
- The complex was significantly more effective against osteospheres than current treatments like cisplatin, carboplatin, and salinomycin.
- Cytotoxicity against OSCs was dependent on cyclooxygenase-2 (COX-2) and involved necroptosis induction, as evidenced by reduced potency with necroptosis inhibitors.
Conclusions:
- The novel nickel(II) complex is a promising agent against osteosarcoma stem cells.
- The compound induces cell death via a mechanism involving both COX-2 and necroptosis.
- This represents the first compound shown to target OSCs through the combined pathways of COX-2 and necroptosis.
