Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF)

Scientific Reports
Wendy HaKerrie L McDonald

Abstract

Recurrence in patients with glioblastoma (GBM) is inevitable resulting in short survival times, even in patients with O-6-Methylguanine-DNA Methyltransferase (MGMT) methylation. Other pathways must be activated to escape from temozolomide (TMZ) treatment, however acquired resistance mechanisms to TMZ are not well understood. Herein, frozen tumors from 36 MGMT methylated patients grouped according to overall survival were extracted and proteins were profiled using surface-enhanced laser desorption/ionization (SELDI) with time-of flight (TOF) proteomics to identify low molecular weight proteins that associated with poor survival outcomes. Overexpression of macrophage migration inhibitory factor (MIF) was identified in human GBM specimens that were MGMT methylated but showed poor survival. This correlation was confirmed in an independent cohort of human GBM. MIF overexpression has been reported in several cancer types, including GBM. We repurposed ibudilast, a specific MIF inhibitor, and treated patient derived cell lines. Ibudilast showed modest anti-proliferative activity however, when combined with TMZ, significant synergism was observed, resulting in cell cycle arrest and apoptosis. In vivo, combined ibudilast and TMZ treatmen...Continue Reading

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Citations

Jun 28, 2019·Frontiers in Immunology·Neibla Priego, Manuel Valiente
Mar 12, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Eugenio CavalliMaria Sofia Basile
Oct 31, 2021·Journal of Hematology & Oncology·Yang XunHua You

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Methods Mentioned

BETA
surgical resection
xenograft
Assay
flow cytometry
chips
protein assay

Software Mentioned

Prism
SPSS
CompuSyn
Mascot search
GraphPad
FlowJo

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