Azathioprine antagonizes aberrantly elevated lipid metabolism and induces apoptosis in glioblastoma
Hye Jin Nam,
Young Eun Kim,
Byoung-San Moon,
Hyun Young Kim,
Daeyoung Jung,
Seungho Choi,
Jeong Woon Jang,
Do-Hyun Nam,
Heeyeong Cho
Affiliations
Hye Jin Nam
Drug Discovery Platform Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
Young Eun Kim
Drug Discovery Platform Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
Byoung-San Moon
Department of Biotechnology, Chonnam National University, Yeosu 59626, Republic of Korea
Hyun Young Kim
Drug Discovery Platform Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
Daeyoung Jung
Drug Discovery Platform Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
Seungho Choi
Drug Discovery Platform Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
Jeong Woon Jang
Drug Discovery Platform Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
Do-Hyun Nam
Department of Neurosurgery, Samsung Medical Center (SMC), Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
Heeyeong Cho
Drug Discovery Platform Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Corresponding author
Summary: Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor with poor survival rate. Temozolomide (TMZ) is used as standard chemotherapy to treat GBM, but a large number of patients either respond poorly and/or develop resistance after long-term use, emphasizing the need to develop potent drugs with novel mechanisms of action. Here, using high-throughput compound screening (HTS), we found that azathioprine, an immunosuppressant, is a promising therapeutic agent to treat TMZ-resistant GBM. Through integrative genome-wide analysis and global proteomic analysis, we found that elevated lipid metabolism likely due to hyperactive EGFR/AKT/SREBP-1 signaling was inhibited by azathioprine. Azathioprine also promoted ER stress-induced apoptosis. Analysis of orthotopic xenograft models injected with patient-derived GBM cells revealed reduced tumor volume and increased apoptosis after azathioprine and TMZ co-treatment. These data indicate that azathioprine could be a powerful therapeutic option for TMZ-resistant GBM patients.
