| 1. |
- Lozano, Maribel, et al.
(författare)
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Cytotoxicity of New Damsin Derivatives in Breast Cancer Cells
- 2019
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Ingår i: Journal of Pharmacy & Drug Development. - 2348-9782. ; 1:2
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Tidskriftsartikel (refereegranskat)abstract
- As a follow-up of a previous investigation in which semisynthetic damsin derivatives were shown to possess up to 10 times higher cytoxicity in JIMT-1 breast cancer cells compared to normal breast epithelial MCF-10A cells, a range of new derivatives were prepared and assayed toward the same cells. Damsin, a natural plant metabolite containing a α-methylene-γ-lactone (or 3-methylenedihydro- furan-2(3H)-one) moiety, was modified in position 3 by Claisen-Schmidt condensations with aromatic aldehydes, mainly mono- or disubstituted benzaldehydes, without affecting the α-methylene-γ-lactone function. This lactone ring is a Michael acceptor that is known to affect biological processes such as cell proliferation, death/apoptosis, and cell migration, by interfering with nucleophilic sites in cell signalling pathways. However, although Michael acceptors are reactive, the Michael addition is reversible and it can be assumed that also other parts of the molecules will moderate the binding to and the release from any given nucleophilic site in a protein, and thereby moderate a specific biological activity. In this investigation, the cytotoxicity of 20 α-methylene-γ-lactones towards normal breast epithelial MCF-10A cells as well as breast cancer JIMT-1 cells is compared, by determining the inhibitory concentration 50 (IC50) from dose response curves. The IC50 values in the two cell lines were found to depend on the overall structure of the assayed compounds, although less in this subset of compounds compared to a previous investigation. Structure-activity relationships that may explain the observed differences in potency and selectivity are discussed.
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| 2. |
- Lozano, Maribel, et al.
(författare)
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Selective Cytotoxicity of Damsin Derivatives in Breast Cancer Cells
- 2019
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Ingår i: Journal of Advanced Pharmaceutical Science and Technology. - : Open Access Pub. - 2328-0182. ; 2:1, s. 23-37
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is the leading cause of death worldwide, and there is a constant need for new treatmentstrategies. Sesquiterpene lactones containing a 3-methylenedihydrofuran-2(3H)-one (or α-methylene-γ-lactone) moiety, for example damsin (1), are Michael acceptors that affect biological processes such as cell proliferation, death/apoptosis, and cell migration, by interfering with cell signalling pathways. Although the reactivity of the α-methylene-γ-lactone moiety is important for these effects, the Michael addition is reversible and it can be assumed that also other parts of the molecules will moderate any given biological activity. In this investigation, the cytotoxicity of 23 α-methylene-γ-lactones towards normal breast epithelial MCF-10A cells as well as breast cancer JIMT-1 cells is compared. Most of the investigated compounds are semisynthetic derivatives prepared by the condensation of the natural product damsin (1) with aldehydes. The two cell lines were treated with various concentrations of the compounds in dose response assays, and the 50 % inhibitory concentration (IC50) was determined from dose response curves. The IC50 values were found to depend strongly on the overall structure. The ratio between the IC50 values for MCF-10A and JIMT-1 cells, as a measure for the selectivity of a compound to kill cancer cells, was calculated, and found to vary between just over 1 to more than 10. The most potent derivatives formed from the condensation of 1 with aromatic aldehydes towards JIMT-1 cells are 3a and 3i, both with ratios between the IC50 values for MCF-10A and JIMT-1 cells close to 5. Also some aldol condensation products with acyclic aldehydes, i.e. 3r and 3u, were equally potent, and the latter showed the highest selectivity (ratio > 10). Structure-activity relationships that may explain the observed differences in potency and selectivity are discussed.
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| 3. |
- Soria Sotillo, Wendy
(författare)
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From ancient herbs to modern drugs : In search of alternatives for cancer therapy
- 2019. - 1
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is the major cause of deaths related to cancer for women worldwide. Although much is known about this malignancy, extensive research is still needed to gain complete understanding of the complexity of the disease. The inter and intra tumor heterogeneity is an important trait of breast cancer. The intratumor heterogeneity is reflected in sub-populations of cancer cells that appear to have different levels of aggressiveness. The most aggressive population termed the cancer stem cell (CSC) population is believed to play a critical role in cancer recurrence and resistance to conventional chemotherapy and CSCs seem to be the responsible for relapse and cancer death. Sesquiterpene lactones (SLs) and methoxyflavones, plant-derived molecules usually found in Asteraceae family plant extracts, have been reported to have anti-inflammatory and anti-cancer activities. This thesis describes the biological activity of natural and synthetized SLs and natural flavones on CSCs and non-CSCs in breast cancer cell lines.Damsin is a natural SL and it was used for the chemical synthesis of damsin derivatives. Here the toxicity of damsin and the damsin derivatives have been investigated in three breast cancer cell lines and one normal-like cell line. In all, 46 compounds were evaluated in dose-response testing to obtain IC50 values that were used to deduce structure activity relationships. Selected SLs were studied further to gain insight into cellular and molecular mechanisms. The studied SLs inhibited cell proliferation and cell migration and remarkably also reduced the CSC population of a breast cancer cell line. The damsin derivatives were more toxic to cancer cells than to normal cells. On the molecular level, the results point to interference of the function of the transcription factor NF-κΒ, being the molecular initiating event. SLs are known to bind to a cysteine in the DNA binding site of NF-κΒ. Our data implicate that it is not only DNA binding of NF-κΒ that is prevented by SL treatment but also the binding of other proteins that have a role in the function of NF-κΒ. The toxicity of three natural methoxyflavones was evaluated revealing that small differences in chemical structure can have a large impact on toxicity. Only one of the methoxyflavones showed anti-proliferative activity in breast cancer cell lines which may be caused by the induction of DNA strand breaks. In contrast to the SLs, treatment with the methoxyflavones did not reduce the CSC population.
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| 4. |
- Sotillo, Wendy Soria, et al.
(författare)
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Anti-cancer stem cell activity of a sesquiterpene lactone isolated from Ambrosia arborescens and of a synthetic derivative
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:9, s. 0184304-0184304
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Tidskriftsartikel (refereegranskat)abstract
- New regimens are constantly being pursued in cancer treatment, especially in the context of treatment-resistant cancer stem cells (CSCs) that are assumed to be involved in cancer recurrence. Here, we investigated the anti-cancer activity of sesquiterpene lactones (SLs) isolated from Ambrosia arborescens and of synthetic derivatives in breast cancer cell lines, with a specific focus on activity against CSCs. The breast cancer cell lines MCF-7, JIMT-1, and HCC1937 and the normal-like breast epithelial cell line MCF-10A were treated with the SLs damsin and coronopilin, isolated from A. arborescens, and with ambrosin and dindol-01, synthesized using damsin. Inhibitory concentration 50 (IC50) values were obtained from dose-response curves. Based on IC50 values, doses in the μM range were used for investigating effects on cell proliferation, cell cycle phase distribution, cell death, micronuclei formation, and cell migration. Western blot analysis was used to investigate proteins involved in cell cycle regulation as well as in the NF-κB pathway since SLs have been shown to inhibit this transcription factor. Specific CSC effects were investigated using three CSC assays. All compounds inhibited cell proliferation; however, damsin and ambrosin were toxic at single-digit micromolar ranges, while higher concentrations were required for coronopilin and dindol-01. Of the four cell lines, the compounds had the least effect on the normal-like MCF-10A cells. The inhibition of cell proliferation can partly be explained by downregulation of cyclin-dependent kinase 2. All compounds inhibited tumour necrosis factor-α-induced translocation of NF-κB from the cytoplasm to the nucleus. Damsin and ambrosin treatment increased the number of micronuclei; moreover, another sign of DNA damage was the increased level of p53. Treatment with damsin and ambrosin decreased the CSC subpopulation and inhibited cell migration. Our results suggest that these compounds should be further investigated to find efficient CSC-inhibiting compounds.
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| 5. |
- Sotillo, Wendy Soria, et al.
(författare)
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Breast cancer cell line toxicity of a flavonoid isolated from Baccharis densiflora
- 2021
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Ingår i: BMC Complementary Medicine and Therapies. - : Springer Science and Business Media LLC. - 2662-7671. ; 21:1
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Tidskriftsartikel (refereegranskat)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 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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