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.
Highlights
Tumor relapse and metastasis remain major obstacles in the improvement of overall cancer survival
Inhibition of the phosphoinositide 3-kinase (PI3K) pathway by PI3K inhibitor LY290042 led to a decrease in CD133+/CD44+ stemlike populations in prostate cancer cell lines [12]. These studies strongly suggest that the PI3K/mTOR pathway is critical for Cancer stem cells (CSCs) maintenance and that targeting PI3K signaling may be beneficial in cancer treatment through eliminating CSCs
The biochemical potency of these compounds against the class I PI3K isoforms was determined with PI3-Kinase Activity ELISA assay, and B591 (Fig. 1a) was identified as a potent pan-PI3K inhibitor
Summary
Tumor relapse and metastasis remain major obstacles in the improvement of overall cancer survival. Inhibition of the PI3K pathway by PI3K inhibitor LY290042 led to a decrease in CD133+/CD44+ stemlike populations in prostate cancer cell lines [12] These studies strongly suggest that the PI3K/mTOR pathway is critical for CSCs maintenance and that targeting PI3K signaling may be beneficial in cancer treatment through eliminating CSCs. In the present study, we designed and synthesized a series of 5-subsitituted dihydrobenzofuran-imidazolium salts compounds and identified a novel specific pan-PI3K inhibitor B591, 3-(2-bromobenzyl)-1-((2,3-dihydrobenzofuran-5-yl)methyl) -5,6-dimethyl-1H-benzo[d] imidazol-3-ium bromide (Fig. 1a), which exhibited approximately equal potency against Class I isoforms of PI3K, while little inhibitory activity was observed in 39 other closely related protein and lipid kinases, indicating the high selectivity towards PI3K. Consistent with the preferential targeting of CSCs, B591 effectively inhibited tumor metastasis and delayed the relapse of breast cancer following cessation of paclitaxel treatment in human breast cancer xenografted models
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
