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


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Article Info

DATE

2019-01-11

AUTHORS

Hongyu Zhou, Chunlei Yu, Lingmei Kong, Xiaoliang Xu, Juming Yan, Yingchao Li, Tao An, Liang Gong, Yaxiao Gong, Huifang Zhu, Hongbin Zhang, Xiaodong Yang, Yan Li

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. More... »

PAGES

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    URI

    http://scigraph.springernature.com/pub.10.1038/s41388-018-0674-5

    DOI

    http://dx.doi.org/10.1038/s41388-018-0674-5

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1111317815

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30635656


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