Journal
BMC COMPLEMENTARY MEDICINE AND THERAPIES
Volume 21, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12906-021-03349-4
Keywords
Flavonoids; Sideritoflavone; Breast cancer; Cytotoxicity; Cell cycle; Cell movement; Cancer stem cells
Categories
Funding
- Research Department of the Swedish International Development Cooperation Agency (SIDA)
- Royal Physiographical Society in Lund
- Lund University
- Kalenderflickorna
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The methoxyflavone sideritoflavone showed high toxicity in all cell lines, inhibiting both CSC and non-CSC sub-populations equally. Treatment with sideritoflavone resulted in cell cycle arrest and DNA double strand breaks, as well as activation of specific signal transduction pathways. Additionally, cell movement was decreased by sideritoflavone treatment.
Background Flavonoids are compounds of interest in the search for new anti-cancer therapies. We have previously isolated the methoxyflavones 5,4 '-dihydroxy-6,7,8,3 '-tetramethoxyflavone (8-methoxycirsilineol), 5,4 '-dihydroxy-6,7,8-trimethoxyflavone (xanthomicrol), and 5,4,'3 '-trihydroxy-6,7,8-trimethoxyflavone (sideritoflavone) from Baccharis densiflora. Herein, we investigate the toxicity of these methoxyflavones in human breast-derived cell line. Our main aim was to focus on the cancer stem cell (CSC) sub-population of JIMT-1 breast cancer cells. Methods Initially, dose response experiments yielding inhibitory concentration 50 (IC50) values were performed using MCF-7, HCC1937, and JIMT-1 breast cancer, and the MCF-10A normal-like breast cell lines to get an understanding of toxic ranges. Due to a clear difference in the toxicity of the flavones, only sideritoflavone was selected for further studies using the JIMT-1 cell line. Effects on the CSC sub-population was investigated using flow cytometry-based methods. A wound healing assay and digital holographic microscopy were used to investigate effects on cell movement. A reporter assay was used to study effects on signal transduction pathways and Western blot for protein expression. Results The dose response data showed that 8-methoxycirsilineol was non-toxic at concentrations below 100 mu M, that the IC50 of xanthomicrol was between 50 and 100 mu M, while sideritoflavone was highly toxic with a single digit mu M IC50 in all cell lines. Treatment of the JIMT-1 cells with 2 mu M sideritoflavone did not selectively effect the CSC sub-population. Instead, sideritoflavone treatment inhibited the proliferation of both the non-CSC and the CSC sub-populations to the same extent. The inhibition of cell proliferation resulted in an accumulation of cells in the G(2) phase of the cell cycle and the treated cells showed an increased level of gamma-H2A histone family member X indicating DNA double strand breaks. Analysis of the effect of sideritoflavone treatment on signal transduction pathways showed activation of the Wnt, Myc/Max, and transforming growth factor-beta pathways. The level of p65/nuclear factor kappa-light-chain-enhancer of activated Beta cells was increased in sideritoflavone-treated cells. Cell movement was decreased by sideritoflavone treatment. Conclusions Altogether our data show that the methoxyflavone sideritoflavone has favourable anti-cancer effects that may be exploited for development to be used in combination with CSC specific compounds.
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