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Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction
Glioblastoma is a primary brain tumor associated with a poor prognosis due to its high chemoresistance capacity. Cancer stem cells (CSCs) are one of the mechanisms of chemoresistance. Although therapy targeting CSCs is promising, strategies targeting CSCs remain unsuccessful. Abnormal activation of...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679129/ https://www.ncbi.nlm.nih.gov/pubmed/31284441 http://dx.doi.org/10.3390/cancers11070947 |
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author | Suzuki, Shuhei Yamamoto, Masahiro Sanomachi, Tomomi Togashi, Keita Sugai, Asuka Seino, Shizuka Yoshioka, Takashi Kitanaka, Chifumi Okada, Masashi |
author_facet | Suzuki, Shuhei Yamamoto, Masahiro Sanomachi, Tomomi Togashi, Keita Sugai, Asuka Seino, Shizuka Yoshioka, Takashi Kitanaka, Chifumi Okada, Masashi |
author_sort | Suzuki, Shuhei |
collection | PubMed |
description | Glioblastoma is a primary brain tumor associated with a poor prognosis due to its high chemoresistance capacity. Cancer stem cells (CSCs) are one of the mechanisms of chemoresistance. Although therapy targeting CSCs is promising, strategies targeting CSCs remain unsuccessful. Abnormal activation of epidermal growth factor receptors (EGFRs) due to amplification, mutation, or both of the EGFR gene is common in glioblastomas. However, glioblastomas are resistant to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and overcoming resistance is essential. Brexpiprazole is a new, safe serotonin-dopamine activity modulator used for schizophrenia and depression that was recently reported to have anti-CSC activity and function as a chemosensitizer. Here, we examined its chemosensitization effects on osimertinib, a third-generation EGFR-TKI with an excellent safety profile, in glioma stem cells (GSCs), which are CSCs of glioblastoma. Brexpiprazole treatment sensitized GSCs to osimertinib and reduced the expression of survivin, an antiapoptotic factor, and the pharmacological and genetic inhibition of survivin mimicked the effects of brexpiprazole. Moreover, co-treatment of brexpiprazole and osimertinib suppressed tumor growth more efficiently than either drug alone without notable toxicity in vivo. This suggests that the combination of brexpiprazole and osimertinib is a potential therapeutic strategy for glioblastoma by chemosensitizing GSCs through the downregulation of survivin expression. |
format | Online Article Text |
id | pubmed-6679129 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-66791292019-08-19 Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction Suzuki, Shuhei Yamamoto, Masahiro Sanomachi, Tomomi Togashi, Keita Sugai, Asuka Seino, Shizuka Yoshioka, Takashi Kitanaka, Chifumi Okada, Masashi Cancers (Basel) Article Glioblastoma is a primary brain tumor associated with a poor prognosis due to its high chemoresistance capacity. Cancer stem cells (CSCs) are one of the mechanisms of chemoresistance. Although therapy targeting CSCs is promising, strategies targeting CSCs remain unsuccessful. Abnormal activation of epidermal growth factor receptors (EGFRs) due to amplification, mutation, or both of the EGFR gene is common in glioblastomas. However, glioblastomas are resistant to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and overcoming resistance is essential. Brexpiprazole is a new, safe serotonin-dopamine activity modulator used for schizophrenia and depression that was recently reported to have anti-CSC activity and function as a chemosensitizer. Here, we examined its chemosensitization effects on osimertinib, a third-generation EGFR-TKI with an excellent safety profile, in glioma stem cells (GSCs), which are CSCs of glioblastoma. Brexpiprazole treatment sensitized GSCs to osimertinib and reduced the expression of survivin, an antiapoptotic factor, and the pharmacological and genetic inhibition of survivin mimicked the effects of brexpiprazole. Moreover, co-treatment of brexpiprazole and osimertinib suppressed tumor growth more efficiently than either drug alone without notable toxicity in vivo. This suggests that the combination of brexpiprazole and osimertinib is a potential therapeutic strategy for glioblastoma by chemosensitizing GSCs through the downregulation of survivin expression. MDPI 2019-07-05 /pmc/articles/PMC6679129/ /pubmed/31284441 http://dx.doi.org/10.3390/cancers11070947 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Suzuki, Shuhei Yamamoto, Masahiro Sanomachi, Tomomi Togashi, Keita Sugai, Asuka Seino, Shizuka Yoshioka, Takashi Kitanaka, Chifumi Okada, Masashi Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction |
title | Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction |
title_full | Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction |
title_fullStr | Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction |
title_full_unstemmed | Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction |
title_short | Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a Third-Generation EGFR-TKI, via Survivin Reduction |
title_sort | brexpiprazole, a serotonin-dopamine activity modulator, can sensitize glioma stem cells to osimertinib, a third-generation egfr-tki, via survivin reduction |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679129/ https://www.ncbi.nlm.nih.gov/pubmed/31284441 http://dx.doi.org/10.3390/cancers11070947 |
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