Abstract
Breast cancer is a major health problem that affects lives worldwide. Breast cancer stem cells (BCSCs) are small subpopulations of cells with capacities for drug resistance, self-renewal, recurrence, metastasis, and differentiation. Herein, powder extracts of beetroot were subjected to silica gel, gel filtration, thin layer chromatography (TLC), and preparatory high-pressure liquid chromatography (HPLC) for isolation of one compound, based on activity-guided purification using tumorsphere formation assays. The purified compound was identified as betavulgarin, using nuclear magnetic resonance spectroscopy and electrospray ionization (ESI) mass spectrometry. Betavulgarin suppressed the proliferation, migration, colony formation, and mammosphere formation of breast cancer cells and reduced the size of the CD44+/CD24− subpopulation and the expression of the self-renewal-related genes, C-Myc, Nanog, and Oct4. This compound decreased the total level and phosphorylated nuclear level of signal transducer and activator of transcription 3 (Stat3) and reduced the mRNA and protein levels of sex determining region Y (SRY)-box 2 (SOX2), in mammospheres. These data suggest that betavulgarin inhibit the Stat3/Sox2 signaling pathway and induces BCSC death, indicating betavulgarin might be an anticancer agent against breast cancer cells and BCSCs.
Highlights
The study of the biological activity of red beetroot (Beta vulgaris rubra) has been growing.Beetroot is a healthy vegetable rich in anthocyanin, betacyanin, folic acid, phenolic compounds, ascorbic acid, flavonoids, vitamin C, and other biologically active components [1,2,3]
To screen and purify breast cancer stem cells (BCSCs) inhibitors from Beta vulgaris rubra, a mammosphere formation assay using MDA-MB-231 cells was performed, and a BCSC inhibitor was purified using methanol extracts of Beta vulgaris rubra generated by ethyl acetate extraction, silica gel filtration, Sephadex LH-20 (GE Healthcare, Uppsala, Sweden) chromatography, preparatory thin-layer chromatography (TLC), and preparatory high-pressure liquid chromatography (HPLC) (Figure 1A)
To ascertain whether betavulgarin has an inhibitory effect on breast cancer growth, we assessed the inhibitory effect of betavulgarin at increased concentrations in MDA-MB-231 and MCF-7 cells
Summary
The study of the biological activity of red beetroot (Beta vulgaris rubra) has been growing. BCSCs are self-renewing and contribute to tumor recurrence; breast cancer stem cells (BCSCs) were first isolated by Al-Hajj [11]. A subpopulation of breast cancer cells exhibit the surface phenotype CD44+ CD24−. The oncogenic transcription factor Signal transducer and activator of transcription 3 (Stat3) is associated with cancer progression, metastasis, chemoresistance, stem cell self-renewal and maintenance, autophagy, and immune evasion [13,14,15]. Many studies have demonstrated that Stat phosphorylation and activation upregulate the expression of cMyc and Sox, which promote the self-renewal of breast cancer cells [17,18,19,20]. We demonstrate that betavulgarin suppresses the proliferation of breast cancer and BCSC formation through the regulation of Stat3/Sox signaling in BCSCs
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