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Nuclear receptor agonists as potential differentiation therapy agents for human osteosarcoma
Rex C Haydon1, Lan Zhou, Tao Feng
1Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Illinois 60637, USA.
Purpose:
This study was designed to investigate whether nuclear receptor agonists can be used as potential differentiation therapy agents for human osteosarcoma.
Experimental Design:
Four osteosarcoma cell lines (143B, MNNG/HOS, MG-63, and TE-85) were treated with proliferator-activated receptor (PPAR)gamma agonists, troglitazone and ciglitazone, and a retinoid X receptor (RXR) ligand, 9-cis retinoic acid. The proliferation and induction of apoptosis in the treated cells were assessed, as was the induction of alkaline phosphatase, a differentiation marker of osteoblasts.
Results:
The expression of PPARgamma was readily detected in all tested osteosarcoma lines. On treatment with the PPARgamma and RXR ligands, all four osteosarcoma lines exhibited a significantly reduced proliferation rate and cell viability. Among the four lines, 143B and MNNG/HOS were shown to be more sensitive to ligand-induced apoptosis, as demonstrated by the Crystal Violet and Hoechst staining assays. Of the three tested ligands, troglitazone was shown to be the most effective in inducing cell death, followed by 9-cis retinoic acid. Moreover, a strong synergistic effect on the induction of cell death was observed when both troglitazone and 9-cis retinoic acid or ciglitazone and 9-cis retinoic acid were administered to osteosarcoma cells. Troglitazone was shown to effectively induce alkaline phosphatase activity, a well-characterized hallmark for osteoblastic differentiation.
Conclusions:
Our findings suggest that PPARgamma and/or RXR ligands may be used as efficacious adjuvant therapeutic agents for primary osteosarcoma, as well as potential chemopreventive agents for preventing the recurrence and metastasis of osteosarcoma after the surgical removal of the primary tumors.
Insights
Nuclear receptor agonists, specifically PPARgamma and RXR ligands, show promise in treating osteosarcoma. These agents effectively reduced cancer cell proliferation and induced apoptosis, suggesting potential as differentiation therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Osteosarcoma is a primary bone cancer with limited treatment options.
- Nuclear receptors play crucial roles in cellular differentiation and proliferation.
- Identifying novel therapeutic strategies for osteosarcoma is a significant clinical need.
Purpose of the Study:
- To investigate the potential of nuclear receptor agonists as differentiation therapy for human osteosarcoma.
- To evaluate the effects of proliferator-activated receptor (PPAR)gamma and retinoid X receptor (RXR) ligands on osteosarcoma cell lines.
Main Methods:
- Four human osteosarcoma cell lines were treated with PPARgamma agonists (troglitazone, ciglitazone) and an RXR ligand (9-cis retinoic acid).
- Assays were performed to assess cell proliferation, apoptosis induction, and alkaline phosphatase activity as a marker of osteoblastic differentiation.
Main Results:
- PPARgamma expression was detected in all osteosarcoma cell lines.
- Treatment with PPARgamma and RXR ligands significantly reduced osteosarcoma cell proliferation and viability.
- Troglitazone and 9-cis retinoic acid induced apoptosis, with synergistic effects observed when combined.
- Troglitazone effectively induced alkaline phosphatase activity, indicating osteoblastic differentiation.
Conclusions:
- PPARgamma and/or RXR ligands demonstrate efficacy as adjuvant therapeutic agents for primary osteosarcoma.
- These ligands may also serve as chemopreventive agents to prevent recurrence and metastasis post-surgery.