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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.
Molecules (Basel, Switzerland)
|May 28, 2022
Summary
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.
