Dihydroartemisinin Potentiates VEGFR-TKIs Antitumorigenic Effect on Osteosarcoma by Regulating Loxl2/VEGFA Expression...

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Anti-angiogenesis therapy is crucial for cancer treatment but faces challenges due to drug resistance.
• Osteosarcoma (OS) remains a challenging cancer with limited treatment options.
• Developing strategies to overcome resistance to anti-angiogenic drugs is critical for improving patient outcomes.

Purpose of the Study:

• To investigate the potential of dihydroartemisinin (DHA) in enhancing anti-angiogenic therapy efficacy in osteosarcoma.
• To elucidate the molecular mechanisms underlying DHA's synergistic effects with anti-angiogenic drugs.

Main Methods:

• Proteomics analysis to identify molecular targets of DHA.
• Quantitative Reverse Transcription Polymerase Chain Reaction (QRT-PCR), Western blot, and Enzyme-Linked Immunosorbent Assay (ELISA) to validate molecular changes.
• Vector-enforced expression studies to confirm gene function.
• Untargeted metabolomic analysis to assess metabolic pathway alterations.

Main Results:

• DHA treatment significantly affected the activity of lysyl oxidase-like 2 (LOXL2) in osteosarcoma cells.
• DHA reduced vascular endothelial growth factor A (VEGFA) expression by downregulating LOXL2.
• DHA interfered with lipid metabolism pathways associated with anti-angiogenic drug resistance.
• DHA demonstrated direct anti-tumor effects and synergistic effects with anti-angiogenic drugs.

Conclusions:

• Dihydroartemisinin (DHA) enhances the efficacy of anti-angiogenic drugs in osteosarcoma by downregulating LOXL2 and VEGFA.
• DHA modulates lipid metabolism, potentially overcoming drug resistance mechanisms.
• DHA represents a promising therapeutic agent for osteosarcoma, offering both direct anti-tumor activity and synergistic effects with existing treatments.