The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway

The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway

Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system. Temozolomide (TMZ)–based adjuvant treatment has improved overall survival, but clinical outcomes remain poor; TMZ resistance is one of the main reasons for this. Here, we report a new phosphatidylinositid...

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Autores principales: Ming Ji, Zhihui Zhang, Songwen Lin, Chunyang Wang, Jing Jin, Nina Xue, Heng Xu, Xiaoguang Chen
Formato: article
Lenguaje:EN
Publicado: Frontiers Media S.A. 2021
Materias:
glioblastoma
TMZ
PI3K
hedgehog
GLI1
Therapeutics. Pharmacology
RM1-950
Acceso en línea:https://doaj.org/article/59f6de3fccf24808aa6aaf913c3d6154
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spelling oai:doaj.org-article:59f6de3fccf24808aa6aaf913c3d61542021-12-01T07:19:41ZThe PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway1663-981210.3389/fphar.2021.749242https://doaj.org/article/59f6de3fccf24808aa6aaf913c3d61542021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.749242/fullhttps://doaj.org/toc/1663-9812Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system. Temozolomide (TMZ)–based adjuvant treatment has improved overall survival, but clinical outcomes remain poor; TMZ resistance is one of the main reasons for this. Here, we report a new phosphatidylinositide 3-kinase inhibitor, XH30; this study aimed to assess the antitumor activity of this compound against TMZ-resistant GBM. XH30 inhibited cell proliferation in TMZ-resistant GBM cells (U251/TMZ and T98G) and induced cell cycle arrest in the G1 phase. In an orthotopic mouse model, XH30 suppressed TMZ-resistant tumor growth. XH30 was also shown to enhance TMZ cytotoxicity both in vitro and in vivo. Mechanistically, the synergistic effect of XH30 may be attributed to its repression of the key transcription factor GLI1 via the noncanonical hedgehog signaling pathway. XH30 reversed sonic hedgehog–triggered GLI1 activation and decreased GLI1 activation by insulin-like growth factor 1 via the noncanonical hedgehog signaling pathway. These results indicate that XH30 may represent a novel therapeutic option for TMZ-resistant GBM.Ming JiMing JiZhihui ZhangSongwen LinChunyang WangJing JinJing JinNina XueHeng XuXiaoguang ChenXiaoguang ChenFrontiers Media S.A.articleglioblastomaTMZPI3KhedgehogGLI1Therapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution DOAJ
collection DOAJ
language EN
topic glioblastoma
TMZ
PI3K
hedgehog
GLI1
Therapeutics. Pharmacology
RM1-950
spellingShingle glioblastoma
TMZ
PI3K
hedgehog
GLI1
Therapeutics. Pharmacology
RM1-950
Ming Ji
Ming Ji
Zhihui Zhang
Songwen Lin
Chunyang Wang
Jing Jin
Jing Jin
Nina Xue
Heng Xu
Xiaoguang Chen
Xiaoguang Chen
The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway
description Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system. Temozolomide (TMZ)–based adjuvant treatment has improved overall survival, but clinical outcomes remain poor; TMZ resistance is one of the main reasons for this. Here, we report a new phosphatidylinositide 3-kinase inhibitor, XH30; this study aimed to assess the antitumor activity of this compound against TMZ-resistant GBM. XH30 inhibited cell proliferation in TMZ-resistant GBM cells (U251/TMZ and T98G) and induced cell cycle arrest in the G1 phase. In an orthotopic mouse model, XH30 suppressed TMZ-resistant tumor growth. XH30 was also shown to enhance TMZ cytotoxicity both in vitro and in vivo. Mechanistically, the synergistic effect of XH30 may be attributed to its repression of the key transcription factor GLI1 via the noncanonical hedgehog signaling pathway. XH30 reversed sonic hedgehog–triggered GLI1 activation and decreased GLI1 activation by insulin-like growth factor 1 via the noncanonical hedgehog signaling pathway. These results indicate that XH30 may represent a novel therapeutic option for TMZ-resistant GBM.
format article
author Ming Ji
Ming Ji
Zhihui Zhang
Songwen Lin
Chunyang Wang
Jing Jin
Jing Jin
Nina Xue
Heng Xu
Xiaoguang Chen
Xiaoguang Chen
author_facet Ming Ji
Ming Ji
Zhihui Zhang
Songwen Lin
Chunyang Wang
Jing Jin
Jing Jin
Nina Xue
Heng Xu
Xiaoguang Chen
Xiaoguang Chen
author_sort Ming Ji
title The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway
title_short The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway
title_full The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway
title_fullStr The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway
title_full_unstemmed The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway
title_sort pi3k inhibitor xh30 enhances response to temozolomide in drug-resistant glioblastoma via the noncanonical hedgehog signaling pathway
publisher Frontiers Media S.A.
publishDate 2021
url https://doaj.org/article/59f6de3fccf24808aa6aaf913c3d6154
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