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. 2017 Jun 6;18(6):1211.
doi: 10.3390/ijms18061211.

Novel Structurally Related Flavones Augment Cell Death Induced by rhsTRAIL

Joanna Bronikowska  1 , Ewelina Szliszka  2 , Edyta Kostrzewa-Susłow  3 , Dagmara Jaworska  4 , Zenon P Czuba  5 , Piotr Bednarski  6 , Wojciech Król  1   7
Affiliations

Novel Structurally Related Flavones Augment Cell Death Induced by rhsTRAIL

Joanna Bronikowska et al. Int J Mol Sci. .

Abstract

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) was identified as a powerful activator of apoptosis in tumor cells and one of the most promising candidates for cancer therapy with no toxicity against normal tissues. However, many tumor cells are resistant to TRAIL-induced apoptosis. The aim of this work was to analyze the improvement of the anticancer effect of rhsTRAIL (recombinant human soluble TRAIL) by nine flavones: 5-Hydroxyflavone, 6-Hydroxyflavone, 7-Hydroxyflavone and their new synthetic derivatives 5-acetoxyflavone, 5-butyryloxyflavone, 6-acetoxyflavone, 6-butyryloxyflavone, 7-acetoxyflavone and 7-butyryloxyflavone. We examined the cytotoxic and apoptotic effects of rhsTRAIL enhanced by novel structurally-related flavones on SW480 and SW620 colon cancer cells using the3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test, the lactate dehydrogenase assay and annexin V-FITC fluorescence staining. We observed a slight difference in the activities of the flavones that was dependent on their chemical structure. Our study indicates that all nine flavones significantly augment cell death by rhsTRAIL (cytotoxicity range 36.8 ± 1.7%-91.4 ± 1.7%; apoptosis increase of 33.0 ± 0.7%-78.5 ± 0.9%). Our study demonstrates the potential use of tested flavones in TRAIL-based anticancer therapy and prevention.

Keywords: TRAIL; apoptosis; cancer cells; cytotoxicity; flavones.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Chemical structures of the tested flavones. HF, Hydroxyflavone; AF, Acetoxyflavone; BF, Butyryloxyflavone.
Figure 2
Figure 2
Cytotoxic and apoptotic effects of rhsTRAIL on SW480 and SW620 colon cancer cells. Cells were incubated with 25–100 ng/mL TRAIL for 48 h. The values represent the mean ± SD of three independent experiments (n = 3). (A) Cytotoxic activity of rhsTRAIL against colon cancer cells. The percentage of cell death was measured using the MTT cytotoxicity assay (*** p < 0.001 compared to control without rhsTRAIL); (B) Apoptotic activity of rhsTRAIL against colon cancer cells. Apoptotic cell death was detected by flow cytometry using annexin V-FITC staining (*** p < 0.001 compared to control without rhsTRAIL).
Figure 3
Figure 3
Cytotoxic effect of rhsTRAIL in combination with flavones on SW480 and SW620 colon cancer cells. Cells were incubated with rhsTRAIL at concentrations of 25–100 ng/mL and/or the compounds at 50 μM and 100 μM for 48 h. The values represent the mean ± SD of three independent experiments (n = 3). The percentage of cell death was measured using the MTT cytotoxicity assay (*** p < 0.001 compared to rhsTRAIL, # p < 0.05, ## p < 0.01 and ### p < 0.001 compared to rhsTRAIL + substrate: 5-HF or 6-HF or 7-HF). Cytotoxic activity of rhsTRAIL with flavones: (A) 5-HF, 5-AF or 5-BF against SW480 cells; (B) 5-HF, 5-AF or 5-BF against SW620 cells; (C) 6-HF, 6-AF or 6-BF against SW480 cells; (D) 6-HF, 6-AF or 6-BF against SW620 cells; (E) 7-HF, 7-AF or 7-BF against SW480; and (F) 7-HF, 7-AF or 7-BF against SW620 cells.
Figure 3
Figure 3
Cytotoxic effect of rhsTRAIL in combination with flavones on SW480 and SW620 colon cancer cells. Cells were incubated with rhsTRAIL at concentrations of 25–100 ng/mL and/or the compounds at 50 μM and 100 μM for 48 h. The values represent the mean ± SD of three independent experiments (n = 3). The percentage of cell death was measured using the MTT cytotoxicity assay (*** p < 0.001 compared to rhsTRAIL, # p < 0.05, ## p < 0.01 and ### p < 0.001 compared to rhsTRAIL + substrate: 5-HF or 6-HF or 7-HF). Cytotoxic activity of rhsTRAIL with flavones: (A) 5-HF, 5-AF or 5-BF against SW480 cells; (B) 5-HF, 5-AF or 5-BF against SW620 cells; (C) 6-HF, 6-AF or 6-BF against SW480 cells; (D) 6-HF, 6-AF or 6-BF against SW620 cells; (E) 7-HF, 7-AF or 7-BF against SW480; and (F) 7-HF, 7-AF or 7-BF against SW620 cells.
Figure 4
Figure 4
Apoptotic effect of rhsTRAIL in combination with flavones on SW480 and SW620 colon cancer cells. Cells were incubated with rhsTRAIL at concentrations of 25–100 ng/mL and/or the compounds at concentrations of 50 μM and 100 μM for 48 h. The values represent the mean ± SD of three independent experiments performed in duplicate (n = 6). Apoptotic cell death was detected by flow cytometry using annexin V-FITC staining (*** p < 0.001 compared to rhsTRAIL, # p < 0.05, ## p < 0.01 and ### p < 0.001 compared to rhsTRAIL + substrate). Apoptotic activity of rhsTRAIL with flavones: (A) 5-HF, 5-AF or 5-BF against SW480 cells; (B) 5-HF, 5-AF or 5-BF against SW620 cells; (C) 6-HF, 6-AF or 6-BF against SW480 cell; (D) 6-HF, 6-AF or 6-BF against SW620 cells; (E) 7-HF, 7-AF or 7-BF against SW480; and (F) 7-HF, 7-AF or 7-BF against SW620 cells.
Figure 4
Figure 4
Apoptotic effect of rhsTRAIL in combination with flavones on SW480 and SW620 colon cancer cells. Cells were incubated with rhsTRAIL at concentrations of 25–100 ng/mL and/or the compounds at concentrations of 50 μM and 100 μM for 48 h. The values represent the mean ± SD of three independent experiments performed in duplicate (n = 6). Apoptotic cell death was detected by flow cytometry using annexin V-FITC staining (*** p < 0.001 compared to rhsTRAIL, # p < 0.05, ## p < 0.01 and ### p < 0.001 compared to rhsTRAIL + substrate). Apoptotic activity of rhsTRAIL with flavones: (A) 5-HF, 5-AF or 5-BF against SW480 cells; (B) 5-HF, 5-AF or 5-BF against SW620 cells; (C) 6-HF, 6-AF or 6-BF against SW480 cell; (D) 6-HF, 6-AF or 6-BF against SW620 cells; (E) 7-HF, 7-AF or 7-BF against SW480; and (F) 7-HF, 7-AF or 7-BF against SW620 cells.
Figure 4
Figure 4
Apoptotic effect of rhsTRAIL in combination with flavones on SW480 and SW620 colon cancer cells. Cells were incubated with rhsTRAIL at concentrations of 25–100 ng/mL and/or the compounds at concentrations of 50 μM and 100 μM for 48 h. The values represent the mean ± SD of three independent experiments performed in duplicate (n = 6). Apoptotic cell death was detected by flow cytometry using annexin V-FITC staining (*** p < 0.001 compared to rhsTRAIL, # p < 0.05, ## p < 0.01 and ### p < 0.001 compared to rhsTRAIL + substrate). Apoptotic activity of rhsTRAIL with flavones: (A) 5-HF, 5-AF or 5-BF against SW480 cells; (B) 5-HF, 5-AF or 5-BF against SW620 cells; (C) 6-HF, 6-AF or 6-BF against SW480 cell; (D) 6-HF, 6-AF or 6-BF against SW620 cells; (E) 7-HF, 7-AF or 7-BF against SW480; and (F) 7-HF, 7-AF or 7-BF against SW620 cells.
Scheme 1
Scheme 1
Synthesis of 5-acetoxyflavone, 6-acetoxyflavone, 7-acetoxyflavone and 5-butyryloxyflavone, 6-butyryloxyflavone, 7-butyryloxyflavone.
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