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

Ha, Wendy, Sevim-Nalkiran, Hatice, Zaman, Ashraf M, Matsuda, Kazuko, Khasraw, Mustafa, Nowak, Anna K, Chung, Liping, Baxter, Robert C and McDonald, Kerrie L 2019, Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF), Scientific reports, vol. 9, pp. 1-10, doi: 10.1038/s41598-019-39427-4.

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Title Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF)
Author(s) Ha, Wendy
Sevim-Nalkiran, Hatice
Zaman, Ashraf M
Matsuda, Kazuko
Khasraw, MustafaORCID iD for Khasraw, Mustafa orcid.org/0000-0003-3249-9849
Nowak, Anna K
Chung, Liping
Baxter, Robert C
McDonald, Kerrie L
Journal name Scientific reports
Volume number 9
Article ID 2905
Start page 1
End page 10
Total pages 10
Publisher Nature Publishing Group
Place of publication London, Eng.
Publication date 2019-02-27
ISSN 2045-2322
Keyword(s) CNS cancer
glioblastoma (GBM)
O-6-Methylguanine-DNA Methyltransferase (MGMT) methylation
temozolomide (TMZ) treatment
Summary 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 treatment of a patient derived xenograft (PDX) model resulted in significantly longer overall survival. Our findings have significant clinical implications for people with GBM. Since clinical trials involving ibudilast have shown no adverse side effects and the drug readily penetrates the blood brain barrier, treatment of GBM with this combination is clinically achievable.
Language eng
DOI 10.1038/s41598-019-39427-4
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2019, The Author(s)
Persistent URL http://hdl.handle.net/10536/DRO/DU:30120712

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
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