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Synergistic HDAC4/8 Inhibition Sensitizes Osteosarcoma to Doxorubicin via pAKT/RUNX2 Pathway Modulation
Anuja Gajanan Magar1,2, Vivek Kumar Morya1,2, Young-Ho Koh3
1School of Medicine, Hallym University, Chuncheon-si 24252, Republic of Korea.
Abstract:
Osteosarcoma is a highly aggressive bone malignancy, particularly challenging in metastatic cases, with a 5-year survival rate remaining under 30%. Although doxorubicin (doxo) is a standard first-line chemotherapeutic agent, its clinical utility is often hindered by the development of drug resistance and associated systemic toxicity. Emerging evidence highlights the role of epigenetic alterations, particularly those involving histone deacetylases (HDACs), in promoting chemoresistance. In this context, the present study aimed to evaluate the therapeutic potential of combining doxo with the selective HDAC inhibitors, tasquinimod (Tas, targeting HDAC4) and PCI-34051 (PCI, targeting HDAC8), in SJSA-1 osteosarcoma cells. Utilizing both 2D and 3D in vitro models, the combination treatment (referred to as the T4 group) significantly reduced cell viability by 57.69% in 2D cultures and decreased spheroid volume by 35.19% in 3D models. The apoptotic response was markedly enhanced, with late apoptosis reaching 64.59% and necrosis at 32.07%, both surpassing the effects observed with doxo alone. Furthermore, wound healing assays demonstrated a 37.74% inhibition of migration, accompanied by a decreased expression of the matrix metalloproteinases MMP9 and MMP13. Mechanistically, the combination therapy led to the downregulation of protein kinase B (pAKT) and RUNX2, along with upregulation of apoptotic markers, including caspase 8, caspase 3, and cleaved caspase 3, indicating a disruption of key survival pathways. These findings suggest that dual HDAC inhibition with Tas and PCI can potentiate doxo efficacy by enhancing apoptosis, inhibiting proliferation, and reducing metastatic potential, thus offering a promising strategy to overcome chemoresistance in osteosarcoma. Further preclinical and clinical studies are required to validate these therapeutic benefits.
Insights
Combining doxorubicin with dual histone deacetylase (HDAC) inhibitors, tasquinimod and PCI-34051, enhances osteosarcoma treatment by increasing apoptosis and reducing cell migration and chemoresistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Osteosarcoma is an aggressive bone cancer with poor survival rates, especially in metastatic cases.
- Doxorubicin (doxo) is a standard chemotherapy but faces challenges due to drug resistance and toxicity.
- Histone deacetylases (HDACs) are implicated in chemoresistance, suggesting them as therapeutic targets.
Purpose of the Study:
- To investigate the combined therapeutic effect of doxorubicin with selective HDAC inhibitors, tasquinimod (Tas) and PCI-34051 (PCI), in osteosarcoma.
- To evaluate the impact of this combination on cell viability, apoptosis, migration, and key molecular pathways.
Main Methods:
- Utilized 2D and 3D in vitro models of SJSA-1 osteosarcoma cells.
- Assessed cell viability, apoptosis, necrosis, and cell migration (wound healing assays).
- Analyzed the expression of key proteins including MMP9, MMP13, pAKT, RUNX2, and caspases.
Main Results:
- The combination treatment (doxo + Tas + PCI) significantly reduced cell viability and spheroid growth compared to doxorubicin alone.
- Enhanced late apoptosis and necrosis, surpassing doxorubicin's effects.
- Inhibited cell migration by 37.74% and decreased MMP9/MMP13 expression.
- Downregulated pAKT and RUNX2, while upregulating caspase 8, caspase 3, and cleaved caspase 3.
Conclusions:
- Dual HDAC inhibition with Tas and PCI potentiates doxorubicin efficacy in osteosarcoma.
- The combination therapy enhances apoptosis, inhibits proliferation, and reduces metastatic potential.
- This strategy shows promise for overcoming chemoresistance in osteosarcoma, warranting further investigation.
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