Azathioprine antagonizes aberrantly elevated lipid metabolism and induces apoptosis in glioblastoma

Area of Science:

• Neuro-oncology
• Cancer Pharmacology
• Molecular Biology

Background:

• Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options.
• Standard chemotherapy drug temozolomide (TMZ) efficacy is often hampered by poor response and acquired resistance.
• Novel therapeutic strategies are urgently needed for TMZ-resistant GBM.

Purpose of the Study:

• To identify novel therapeutic agents for temozolomide-resistant glioblastoma multiforme.
• To investigate the mechanism of action of azathioprine in TMZ-resistant GBM.

Main Methods:

• High-throughput compound screening (HTS) was employed to identify potential drug candidates.
• Integrative genome-wide and global proteomic analyses were performed.
• Orthotopic xenograft models using patient-derived GBM cells were utilized for in vivo validation.

Main Results:

• Azathioprine, an immunosuppressant, demonstrated efficacy against TMZ-resistant GBM.
• Azathioprine was found to inhibit elevated lipid metabolism by targeting the EGFR/AKT/SREBP-1 signaling pathway.
• Azathioprine induced endoplasmic reticulum (ER) stress and promoted apoptosis in GBM cells.
• Co-treatment with azathioprine and TMZ reduced tumor volume and increased apoptosis in preclinical models.

Conclusions:

• Azathioprine represents a promising therapeutic agent for patients with temozolomide-resistant glioblastoma multiforme.
• Targeting lipid metabolism and inducing apoptosis are key mechanisms of azathioprine's anti-cancer activity.
• Azathioprine warrants further investigation as a potential treatment for refractory GBM.