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Updated: Jun 4, 2026
Cytotoxic Efficacy of Photodynamic Therapy in Osteosarcoma Cells In Vitro
Published on: March 18, 2014
Bisphosphonate enhances TRAIL sensitivity to human osteosarcoma cells via death receptor 5 upregulation
Myung Hee Moon1, Jae Kyo Jeong, Jae Suk Seo
1Center for Healthcare Technology Development ,Bio-Safety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Korea.
Abstract:
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily of cytokines, is one of the most promising candidates for cancer therapeutics. However, many osteosarcomas are resistant to TRAIL. Bisphosphonates are very effective in the treatment of bone problems associated with malignancies; the antitumor effects are due to the inhibition of protein prenylation that is essential for cell function and survival. The purpose of this study was to determine the effects of bisphosphonates on TRAIL-resistant MG 63 human osteosarcoma cells. The cells showed no response to TRAIL alone; however, pre-treatment with bisphosphonates significantly increased TRAIL-mediated apoptosis and cellular activation of caspase-3. Bisphosphonates significantly induced mRNA and protein expression of the TRAIL receptor, DR5. Bisphosphonates induced protein unprenylation in MG 63 cells; in addition, co-treatment with TRAIL also significantly increased protein unprenylation. Blocking of protein unprenylation using geranylgeraniol attenuated the cellular responses, including cell apoptosis and protein unprenylation induced by bisphosphonates and TRAIL. This is the first study to demonstrate that bisphosphonates markedly enhanced TRAIL-induced apoptosis in human osteosarcoma cells. These findings suggest that bisphosphonates may be a new and effective anticancer treatment with TRAIL proteins for TRAIL-resistant cancer cells.
Insights
Bisphosphonates enhance the effectiveness of Tumor Necrosis Factor (TNF)-related apoptosis-inducing ligand (TRAIL) therapy in osteosarcoma. This combination overcomes TRAIL resistance by increasing apoptosis and DR5 receptor expression in cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic, but osteosarcomas often exhibit resistance.
- Bisphosphonates inhibit protein prenylation, crucial for cell survival, and are used for bone-related malignancies.
Purpose of the Study:
- To investigate the effects of bisphosphonates on TRAIL-resistant human osteosarcoma cells (MG 63).
- To determine if bisphosphonates can sensitize osteosarcoma cells to TRAIL-induced apoptosis.
Main Methods:
- MG 63 cells were treated with bisphosphonates, TRAIL, or a combination.
- Assays were performed to measure apoptosis, caspase-3 activation, DR5 receptor expression (mRNA and protein), and protein unprenylation.
- Geranylgeraniol was used to block protein unprenylation.
Main Results:
- Osteosarcoma cells resistant to TRAIL alone showed increased apoptosis and caspase-3 activation upon bisphosphonate pre-treatment.
- Bisphosphonates significantly upregulated the expression of the TRAIL receptor DR5.
- Bisphosphonates induced protein unprenylation, which was further enhanced by co-treatment with TRAIL. Blocking unprenylation attenuated these effects.
Conclusions:
- Bisphosphonates significantly enhance TRAIL-induced apoptosis in TRAIL-resistant human osteosarcoma cells.
- This study demonstrates a novel therapeutic strategy combining bisphosphonates with TRAIL for overcoming cancer cell resistance.
