Screening for Synergistic Reagents With Pazopanib Against Osteosarcoma Using a Compound Library

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Osteosarcoma (OS) is the most common primary bone malignancy.
• Current therapeutic agents for OS have been in use since the 1970s, necessitating novel treatment strategies.
• Pazopanib (PZP) has shown clinical efficacy in metastatic OS.

Purpose of the Study:

• To investigate novel therapeutic approaches for osteosarcoma.
• To evaluate the combination treatment of pazopanib (PZP) with other candidate agents.
• To assess the effects of combined therapy on tumor growth in an in vivo model.

Main Methods:

• Screening of 324 compounds in combination with PZP against MG63 OS cells.
• Assessment of cell viability and antiproliferative effects on four OS cell lines.
• Evaluation of cell signaling pathways via western blot and in vivo antitumor testing in 143B-bearing mice.

Main Results:

• Crizotinib (CRZ) was identified as the most effective agent for combination with PZP.
• The PZP and CRZ combination demonstrated synergistic antitumor effects compared to single agents or control.
• Dual therapy downregulated c-MYC, p-AKT, p-STAT3, p-cyclin D1, and survivin, while upregulating cleaved caspase-3 and cleaved PARP, indicating apoptosis induction.

Conclusions:

• Combined pazopanib (PZP) and crizotinib (CRZ) exhibit synergistic anti-tumor activity against osteosarcoma.
• The combination induces apoptosis both in vitro and in vivo, potentially through the downregulation of AKT and STAT3 signaling.
• These findings suggest that the PZP and CRZ combination is a viable therapeutic option for clinical application in osteosarcoma patients.