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

doi:10.1038/s41388-018-0674-5

	B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells
	Zhou, Hongyu 1; Yu, Chunlei 1,2; Kong, Lingmei 1; Xu, Xiaoliang 3; Yan, Juming 1,4; Li, Yingchao 3; An, Tao1,5 ; Gong, Liang 1,4; Gong, Yaxiao 1,4; Zhu, Huifang 1,4; Zhang, Hongbin 3; Yang, Xiaodong 3; Li, Yan1,5
Corresponding Author	Zhang, Hongbin(zhanghb@ynu.edu.cn) ; Yang, Xiaodong(xdyang@ynu.edu.cn) ; Li, Yan(liyanb@mail.kib.ac.cn)
	2019-05-02
Source Publication	ONCOGENE
ISSN	0950-9232
Volume	38 Issue:18 Pages:3371-3386
Abstract	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.
DOI	10.1038/s41388-018-0674-5
Indexed By	SCI
Language	英语
WOS ID	WOS:000466610000004
Citation statistics
Document Type	期刊论文
Identifier	http://ir.kib.ac.cn/handle/151853/66775
Collection	植物化学与西部植物资源持续利用国家重点实验室
Corresponding Author	Zhang, Hongbin; Yang, Xiaodong; Li, Yan
Affiliation	1.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming, Yunnan, Peoples R China 2.North Sichuan Med Coll, Sch Pharm, Inst Mat Med, Nanchong, Peoples R China 3.Yunnan Univ, Sch Chem Sci & Technol, Minist Educ & Yunnan Prov, Key Lab Med Chem Nat Resource, Kunming, Yunnan, Peoples R China 4.Univ Chinese Acad Sci, Beijing, Peoples R China 5.Chinese Acad Sci, Kunming Inst Bot, Yunnan Key Lab Nat Med Chem, Kunming, Yunnan, Peoples R China
Recommended Citation GB/T 7714	Zhou, Hongyu,Yu, Chunlei,Kong, Lingmei,et al. B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells[J]. ONCOGENE,2019,38(18):3371-3386.
APA	Zhou, Hongyu.,Yu, Chunlei.,Kong, Lingmei.,Xu, Xiaoliang.,Yan, Juming.,...&Li, Yan.(2019).B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells.ONCOGENE,38(18),3371-3386.
MLA	Zhou, Hongyu,et al."B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells".ONCOGENE 38.18(2019):3371-3386.

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