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Cancer stem cells (CSCs) have been recognized as rare populations driving cancer progression, metastasis, and drug resistance in leading cancers. Attempts have been made toward identifying compounds that specifically target these CSCs. Therefore, investigations of novel therapeutic strategies for CSC targeting are required. The cytotoxic effects of chrysotoxine on human non-small cell lung cancer-derived H460 and H23 cells were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effects of chrysotoxine suppression of CSC-like phenotypes were determined in CSC-rich populations and primary CSCs in three-dimensional (3D) culture and in an extreme limiting dilution assay. Expression of CSC markers and associated proteins was determined by Western blot analyse and flow cytometry. We have reported herein the CSC-suppressing activity of chrysotoxine, a bibenzyl compound isolated from Dendrobium pulchellum We have shown, to our knowledge for the first time, that chrysotoxine dramatically suppresses CSC-like phenotypes of H460 and H23 cells. Treatment with chrysotoxine significantly reduced the viability of 3D CSC-rich populations and concomitantly decreased known CSC markers. Chrysotoxine suppressed CSC phenotypes through downregulation of Src/protein kinase B (Akt) signaling. Active (phosphorylated Y416) Src was shown to regulate cancer stemness, since ectopic overexpression of Src strongly activated Akt and subsequently enhanced pluripotency transcription factor SRY (sex-determining region Y)-box 2 (Sox2)- mediating CSC phenotypes, whereas the short hairpin RNA of Src and an Src inhibitor (dasatinib) suppressed Akt, Sox2, and CSC properties. Importantly, chrysotoxine was shown to suppress active Src/Akt signaling and in turn depleted Sox2-mediated CSCs. Our findings indicate a novel CSC-targeted role of chrysotoxine and its regulation by Src/Akt and Sox2, which may be exploited for cancer treatment.

Cancer Stem Cell–Suppressing Activity of Chrysotoxine, a Bibenzyl fromDendrobium pulchellum