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Breast cancer cell line toxicity of a flavonoid isolated from Baccharis densiflora

Sotillo, Wendy Soria LU ; Tarqui, Santiago ; Huang, Xiaoli LU ; Almanza, Giovanna and Oredsson, Stina LU (2021) In BMC Complementary Medicine and Therapies 21(1).
Abstract

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... (More)

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 μM, that the IC50 of xanthomicrol was between 50 and 100 μM, while sideritoflavone was highly toxic with a single digit μM IC50 in all cell lines. Treatment of the JIMT-1 cells with 2 μM 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 G2 phase of the cell cycle and the treated cells showed an increased level of γ-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-β pathways. The level of p65/nuclear factor kappa-light-chain-enhancer of activated Β 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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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Breast cancer, Cancer stem cells, Cell cycle, Cell movement, Cytotoxicity, Flavonoids, Sideritoflavone
in
BMC Complementary Medicine and Therapies
volume
21
issue
1
article number
188
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85109188115
  • pmid:34215226
ISSN
2662-7671
DOI
10.1186/s12906-021-03349-4
language
English
LU publication?
yes
id
ee2b94e7-bf2a-446b-893d-555fc2117ea4
date added to LUP
2021-08-12 11:06:04
date last changed
2024-06-15 14:14:35
@article{ee2b94e7-bf2a-446b-893d-555fc2117ea4,
  abstract     = {{<p>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 (IC<sub>50</sub>) 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 μM, that the IC<sub>50</sub> of xanthomicrol was between 50 and 100 μM, while sideritoflavone was highly toxic with a single digit μM IC<sub>50</sub> in all cell lines. Treatment of the JIMT-1 cells with 2 μM 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<sub>2</sub> phase of the cell cycle and the treated cells showed an increased level of γ-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-β pathways. The level of p65/nuclear factor kappa-light-chain-enhancer of activated Β 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.</p>}},
  author       = {{Sotillo, Wendy Soria and Tarqui, Santiago and Huang, Xiaoli and Almanza, Giovanna and Oredsson, Stina}},
  issn         = {{2662-7671}},
  keywords     = {{Breast cancer; Cancer stem cells; Cell cycle; Cell movement; Cytotoxicity; Flavonoids; Sideritoflavone}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{BMC Complementary Medicine and Therapies}},
  title        = {{Breast cancer cell line toxicity of a flavonoid isolated from Baccharis densiflora}},
  url          = {{http://dx.doi.org/10.1186/s12906-021-03349-4}},
  doi          = {{10.1186/s12906-021-03349-4}},
  volume       = {{21}},
  year         = {{2021}},
}