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B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells

Cancer stem cells (CSCs) have been implicated in metastasis, relapse, and therapeutic resistance of cancer, so successful cancer therapy may therefore require the development of drugs against CSCs or combining anti-CSCs drugs with conventional therapies. The phosphoinositide 3-kinase (PI3K) signalin...

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Autores principales: Zhou, Hongyu, Yu, Chunlei, Kong, Lingmei, Xu, Xiaoliang, Yan, Juming, Li, Yingchao, An, Tao, Gong, Liang, Gong, Yaxiao, Zhu, Huifang, Zhang, Hongbin, Yang, Xiaodong, Li, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756013/
https://www.ncbi.nlm.nih.gov/pubmed/30635656
http://dx.doi.org/10.1038/s41388-018-0674-5
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author Zhou, Hongyu
Yu, Chunlei
Kong, Lingmei
Xu, Xiaoliang
Yan, Juming
Li, Yingchao
An, Tao
Gong, Liang
Gong, Yaxiao
Zhu, Huifang
Zhang, Hongbin
Yang, Xiaodong
Li, Yan
author_facet Zhou, Hongyu
Yu, Chunlei
Kong, Lingmei
Xu, Xiaoliang
Yan, Juming
Li, Yingchao
An, Tao
Gong, Liang
Gong, Yaxiao
Zhu, Huifang
Zhang, Hongbin
Yang, Xiaodong
Li, Yan
author_sort Zhou, Hongyu
collection PubMed
description Cancer stem cells (CSCs) have been implicated in metastasis, relapse, and therapeutic resistance of cancer, so successful cancer therapy may therefore require the development of drugs against CSCs or combining anti-CSCs drugs with conventional therapies. The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently activated signaling pathways in human cancer, playing a central role in tumorigenesis as well as the maintenance of CSCs. Here, we designed and identified B591, a dihydrobenzofuran-imidazolium salt, as a novel specific pan-PI3K inhibitor with potent inhibitory activity against class I PI3K isoforms, which showed effective inhibition of cellular PI3K/mTOR signaling pathway and robust antitumor activity in a set of cancer cell lines. Notably, compared with bulk tumor cell populations, B591 exhibited more potency in suppressing CSCs survival and inducing CSCs apoptosis, and presence of B591 effectively eliminated paclitaxel-enriched CSCs. B591 diminished self-renewal capacity and decreased the expression of epithelial-mesenchymal transition (EMT) markers of CSCs. In vivo, B591 preferentially decreased CSCs levels in mouse xenograft model of human breast cancer as evidenced especially by remarkable reduction of tumor-initiating ability. Consistent with the preferential targeting of CSCs, B591 effectively inhibited breast tumor metastasis and delayed tumor regrowth following paclitaxel treatment. Taken together, our findings establish B591, a novel PI3K inhibitor, as a strong candidate for clinical evaluation as a CSCs targeting agent.
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spelling pubmed-67560132019-09-24 B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells Zhou, Hongyu Yu, Chunlei Kong, Lingmei Xu, Xiaoliang Yan, Juming Li, Yingchao An, Tao Gong, Liang Gong, Yaxiao Zhu, Huifang Zhang, Hongbin Yang, Xiaodong Li, Yan Oncogene Article Cancer stem cells (CSCs) have been implicated in metastasis, relapse, and therapeutic resistance of cancer, so successful cancer therapy may therefore require the development of drugs against CSCs or combining anti-CSCs drugs with conventional therapies. The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently activated signaling pathways in human cancer, playing a central role in tumorigenesis as well as the maintenance of CSCs. Here, we designed and identified B591, a dihydrobenzofuran-imidazolium salt, as a novel specific pan-PI3K inhibitor with potent inhibitory activity against class I PI3K isoforms, which showed effective inhibition of cellular PI3K/mTOR signaling pathway and robust antitumor activity in a set of cancer cell lines. Notably, compared with bulk tumor cell populations, B591 exhibited more potency in suppressing CSCs survival and inducing CSCs apoptosis, and presence of B591 effectively eliminated paclitaxel-enriched CSCs. B591 diminished self-renewal capacity and decreased the expression of epithelial-mesenchymal transition (EMT) markers of CSCs. In vivo, B591 preferentially decreased CSCs levels in mouse xenograft model of human breast cancer as evidenced especially by remarkable reduction of tumor-initiating ability. Consistent with the preferential targeting of CSCs, B591 effectively inhibited breast tumor metastasis and delayed tumor regrowth following paclitaxel treatment. Taken together, our findings establish B591, a novel PI3K inhibitor, as a strong candidate for clinical evaluation as a CSCs targeting agent. Nature Publishing Group UK 2019-01-11 2019 /pmc/articles/PMC6756013/ /pubmed/30635656 http://dx.doi.org/10.1038/s41388-018-0674-5 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
Zhou, Hongyu
Yu, Chunlei
Kong, Lingmei
Xu, Xiaoliang
Yan, Juming
Li, Yingchao
An, Tao
Gong, Liang
Gong, Yaxiao
Zhu, Huifang
Zhang, Hongbin
Yang, Xiaodong
Li, Yan
B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells
title B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells
title_full B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells
title_fullStr B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells
title_full_unstemmed B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells
title_short B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells
title_sort b591, a novel specific pan-pi3k inhibitor, preferentially targets cancer stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756013/
https://www.ncbi.nlm.nih.gov/pubmed/30635656
http://dx.doi.org/10.1038/s41388-018-0674-5
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