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

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 TM...

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Autores principales: Ha, Wendy, Sevim-Nalkiran, Hatice, Zaman, Ashraf M., Matsuda, Kazuko, Khasraw, Mustafa, Nowak, Anna K., Chung, Liping, Baxter, Robert C., McDonald, Kerrie L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393433/
https://www.ncbi.nlm.nih.gov/pubmed/30814573
http://dx.doi.org/10.1038/s41598-019-39427-4
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author Ha, Wendy
Sevim-Nalkiran, Hatice
Zaman, Ashraf M.
Matsuda, Kazuko
Khasraw, Mustafa
Nowak, Anna K.
Chung, Liping
Baxter, Robert C.
McDonald, Kerrie L.
author_facet Ha, Wendy
Sevim-Nalkiran, Hatice
Zaman, Ashraf M.
Matsuda, Kazuko
Khasraw, Mustafa
Nowak, Anna K.
Chung, Liping
Baxter, Robert C.
McDonald, Kerrie L.
author_sort Ha, Wendy
collection PubMed
description 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.
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spelling pubmed-63934332019-03-01 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. McDonald, Kerrie L. Sci Rep Article 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. Nature Publishing Group UK 2019-02-27 /pmc/articles/PMC6393433/ /pubmed/30814573 http://dx.doi.org/10.1038/s41598-019-39427-4 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ha, Wendy
Sevim-Nalkiran, Hatice
Zaman, Ashraf M.
Matsuda, Kazuko
Khasraw, Mustafa
Nowak, Anna K.
Chung, Liping
Baxter, Robert C.
McDonald, Kerrie L.
Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF)
title Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF)
title_full Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF)
title_fullStr Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF)
title_full_unstemmed Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF)
title_short Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF)
title_sort ibudilast sensitizes glioblastoma to temozolomide by targeting macrophage migration inhibitory factor (mif)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393433/
https://www.ncbi.nlm.nih.gov/pubmed/30814573
http://dx.doi.org/10.1038/s41598-019-39427-4
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