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
• Publication Date: 2022-10-06T16:56:29Z
• Authors: Dong Yang; Zhi Dai; Peifeng Zhu; Gan Wang; Bin Sun; Shirong Li; Junjun Hao; Yifen Wang; Yaping Liu; Shuaishuai Yu; Ren Lai; Xiao-Dong Luo; Xudong Zhao
• Keywords: 0303 health sciences; Antineoplastic Agents; Carbon; 3. Good health; 03 medical and health sciences; Tandem Mass Spectrometry; Cell Line, Tumor; Neoplastic Stem Cells; Humans; Glioblastoma; Early Detection of Cancer; Chromatography, Liquid; Cell Proliferation

Cancer stem cells (CSCs) are characterized by their ability to self-renew, 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 potential usefulness as a cancer treatment through cytotoxic actions on CSCs.Here, we identify CSC-specific derived from products characterize putative mechanisms action in CSCs.Glioblastoma (GSCs) were labeled with EGFP via homologous recombination utilized high-throughput screen 8,344 fractions 386 herbal medicines. The that extinguished fluorescence signal then further LC-MS/MS. Next, several evaluated effects GSCs, lines immortalized using variety methods study proliferation (EdU incorporation assay), death (cleaved-Caspase-3 immunostaining), DNA damage (comet mitochondrial membrane changes (JC-1 formation vitro (soft agar colony forming assay). We performed surface plasmon resonance analysis, western blotting, immunohistochemistry the underlying GSCs. Finally, carried out xenograft growth assays candidates vivo.Our high throughput led identification furostanol saponin taccaoside A its two homologs rhizomatous geophyte Tacca. subflabellata Interestingly, effect was less compared homologs, owing stereochemical differences carbon-carbon double bond between C-20 C-22. Molecular revealed binds RAS inhibit downstream effector signaling. Correspondingly, blockade interaction abolished inhibitory this compound CSCs. Furthermore, effective limiting yielded an approach agents. Through approach, identified CSCs molecular mechanism involves binding suppression Our findings indicate is lead anti-CSC drug discovery.