High throughput-screening of native herbal compounds identifies taccaoside A as a cytotoxic compound that mediates RAS signaling in cancer stem cells

doi:10.1016/j.phymed.2022.154492

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	High throughput-screening of native herbal compounds identifies taccaoside A as a cytotoxic compound that mediates RAS signaling in cancer stem cells
	Yang,Dong; Dai,Zhi; Zhu,Peifeng; Wang,Gan; Sun,Bin; Li,Shirong; Hao,Junjun; Wang,Yifen; Liu,Yaping; Yu,Shuaishuai; Lai,Ren; Luo,Xiao-Dong; Zhao,Xudong
	2023
发表期刊	PHYTOMEDICINE
ISSN	1618-095X
卷号	108 页码:154492
摘要	Background: Cancer stem cells (CSCs) are characterized by their ability to self-renew, to differentiate into multiple cell types and also drive tumor formation, altogether making them important cellular targets for therapeutic intervention. However, existing CSC-targeting drugs do not significantly improve clinical outcomes. More recently, preclinical studies of natural product-derived compounds have demonstrated their potential usefulness as a therapeutic cancer treatment through their cytotoxic actions on CSCs. Purpose: Here, we identify CSC-specific compounds derived from natural products and characterize their pu-tative mechanisms of action in CSCs. Methods: Glioblastoma stem cells (GSCs) were labeled with EGFP via homologous recombination and utilized for a high-throughput screen of 8,344 fractions from 386 herbal medicines. The fractions that extinguished EGFP fluorescence signal were then further characterized by LC-MS/MS. Next, several putative cytotoxic compounds were evaluated for their cytotoxic effects on GSCs, cancer cell lines and immortalized cells using a variety of methods to study cell proliferation (EdU incorporation assay), cell death (cleaved-Caspase-3 immunostaining), DNA damage (comet assay), mitochondrial membrane changes (JC-1 immunostaining), and tumor formation in vitro (soft agar colony forming assay). We also performed surface plasmon resonance analysis, western blotting, and immunohistochemistry to characterize the putative mechanisms underlying the cytotoxic effects of putative compounds on GSCs. Finally, we carried out xenograft tumor growth assays to study the cytotoxic potential of several candidates in vivo. Results: Our high throughput screen led to the identification of the furostanol saponin taccaoside A and its two homologs from the rhizomatous geophyte Tacca. subflabellata that were cytotoxic to GSCs. Interestingly, the cytotoxic effect of taccaoside A on cell lines was significantly less compared to its homologs, owing to stereo -chemical differences of a carbon-carbon double bond between C-20 and C-22. Molecular studies revealed that taccaoside A binds to RAS to inhibit downstream effector signaling. Correspondingly, blockade of the interaction between taccaoside A and RAS abolished the inhibitory effect of this compound on CSCs. Furthermore, tac-caoside A treatment was effective in limiting tumor cell growth in vivo. Conclusion: Our study yielded an effective approach to screen for CSC-specific agents. Through this approach, we identified taccaoside A from the rhizomatous geophyte Tacca. subflabellata are cytotoxic to CSCs through a molecular mechanism that involves RAS binding and suppression of its downstream signaling. Our findings indicate taccaoside A is a potential lead compound for anti-CSC drug discovery.
关键词	Natural product Furostanol saponin Taccaoside A Cancer stem cell RAS STEROIDAL SAPONINS NATURAL-PRODUCTS PI3K/AKT PROLIFERATION MAINTENANCE STATISTICS MAPK/ERK
学科领域	Plant Sciences ; Pharmacology & Pharmacy ; Integrative & Complementary Medicine
DOI	10.1016/j.phymed.2022.154492
收录类别	SCI
WOS记录号	WOS:000930554400001
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75400
专题	中国科学院昆明植物研究所
推荐引用方式 GB/T 7714	Yang,Dong,Dai,Zhi,Zhu,Peifeng,et al. High throughput-screening of native herbal compounds identifies taccaoside A as a cytotoxic compound that mediates RAS signaling in cancer stem cells[J]. PHYTOMEDICINE,2023,108:154492.
APA	Yang,Dong.,Dai,Zhi.,Zhu,Peifeng.,Wang,Gan.,Sun,Bin.,...&Zhao,Xudong.(2023).High throughput-screening of native herbal compounds identifies taccaoside A as a cytotoxic compound that mediates RAS signaling in cancer stem cells.PHYTOMEDICINE,108,154492.
MLA	Yang,Dong,et al."High throughput-screening of native herbal compounds identifies taccaoside A as a cytotoxic compound that mediates RAS signaling in cancer stem cells".PHYTOMEDICINE 108(2023):154492.

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