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.

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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