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Cytotoxic Efficacy of Photodynamic Therapy in Osteosarcoma Cells In Vitro
Published on: March 18, 2014
Sensitivity of osteosarcoma cells to HDAC inhibitor AR-42 mediated apoptosis
Sridhar Murahari1, Aimee L Jalkanen1,2, Samuel K Kulp3
1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, 43210, USA.
Background:
Osteosarcoma (OS) is the most common primary bone tumor in both humans and dogs and is the second leading cause of cancer related deaths in children and young adults. Limb sparing surgery along with chemotherapy has been the mainstay of treatment for OS. Many patients are not cured with current therapies, presenting a real need for developing new treatments. Histone deacetylase (HDAC) inhibitors are a promising new class of anticancer agents. In this study, we investigated the activity of the novel HDAC inhibitor AR-42 in a panel of human and canine OS cell lines.
Methods:
The effect of AR-42 and suberoylanilide hydroxamic acid (SAHA) alone or in combination with doxorubicin on OS cell viability was assessed. Induction of histone acetylation after HDAC inhibitor treatment was confirmed by Western blotting. Drug-induced apoptosis was analyzed by FACS. Apoptosis was assessed further by measuring caspase 3/7 enzymatic activity, nucleosome fragmentation, and caspase cleavage. Effects on Akt signaling were demonstrated by assessing phosphorylation of Akt and downstream signaling molecules.
Results:
AR-42 was a potent inhibitor of cell viability and induced a greater apoptotic response compared to SAHA when used at the same concentrations. Normal osteoblasts were much less sensitive. The combination of AR-42 with doxorubicin resulted in a potent inhibition of cell viability and apparent synergistic effect. Furthermore, we showed that AR-42 and SAHA induced cell death via the activation of the intrinsic mitochondrial pathway through activation of caspase 3/7. This potent apoptotic activity was associated with the greater ability of AR-42 to downregulate survival signaling through Akt.
Conclusions:
These results confirm that AR-42 is a potent inhibitor of HDAC activity and demonstrates its ability to significantly inhibit cell survival through its pleiotropic effects in both canine and human OS cells and suggests that spontaneous OS in pet dogs may be a useful large animal model for preclinical evaluation of HDAC inhibitors. HDAC inhibition in combination with standard doxorubicin treatment offers promising potential for chemotherapeutic intervention in both canine and human OS.
Insights
The novel HDAC inhibitor AR-42 effectively reduced osteosarcoma cell viability and induced apoptosis in both human and canine cell lines. AR-42 combined with doxorubicin showed synergistic effects, suggesting potential for new cancer treatments.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Osteosarcoma (OS) is a common bone cancer in humans and dogs, with limited treatment options.
- Current therapies like surgery and chemotherapy often fail to cure OS.
- Histone deacetylase (HDAC) inhibitors represent a promising new class of anticancer agents.
Purpose of the Study:
- To investigate the efficacy of a novel HDAC inhibitor, AR-42, against human and canine osteosarcoma cell lines.
- To compare AR-42's activity with another HDAC inhibitor, SAHA.
- To evaluate the combination of AR-42 with doxorubicin for enhanced anti-cancer effects.
Main Methods:
- Assessed cell viability and apoptosis (caspase 3/7 activity, nucleosome fragmentation) after treatment with AR-42, SAHA, and doxorubicin.
- Confirmed histone acetylation induction via Western blotting.
- Analyzed effects on Akt signaling pathway phosphorylation.
Main Results:
- AR-42 potently inhibited cell viability and induced apoptosis more effectively than SAHA at equivalent concentrations.
- AR-42 and doxorubicin demonstrated a synergistic effect, significantly inhibiting cell viability.
- AR-42 and SAHA triggered apoptosis through the intrinsic mitochondrial pathway and downregulated Akt survival signaling.
Conclusions:
- AR-42 is a potent HDAC inhibitor that significantly inhibits osteosarcoma cell survival via multiple mechanisms.
- Canine OS models may be valuable for preclinical evaluation of HDAC inhibitors.
- Combining HDAC inhibitors with doxorubicin shows promise for treating both canine and human osteosarcoma.
