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Long Term Exposure to Polyphenols of Artichoke (Cynara scolymus L.) Exerts Induction of Senescence Driven Growth Arrest in the MDA-MB231 Human Breast Cancer Cell Line.

Mileo AM, Di Venere D, Abbruzzese C, Miccadei S - Oxid Med Cell Longev (2015)

Bottom Line: Furthermore, AEs exposure induces a significant increase of senescence-associated β-galactosidase (SA-β-gal) staining and upregulation of tumour suppressor genes, p16(INK4a) and p21(Cip1/Waf1) in MDA-MB231 cells.Inhibition of ROS generation by N-acetylcysteine (NAC) attenuates the antiproliferative effect.Our results suggest that artichoke polyphenols could be a promising dietary tool either in cancer chemoprevention or/and in cancer treatment as a nonconventional, adjuvant therapy.

View Article: PubMed Central - PubMed

Affiliation: Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy.

ABSTRACT
Polyphenolic extracts from the edible part of artichoke (Cynara scolymus L.) have been shown to be potential chemopreventive and anticancer dietary compounds. High doses of polyphenolic extracts (AEs) induce apoptosis and decrease the invasive potential of the human breast cancer cell line, MDA-MB231. However, the molecular mechanism underlying AEs antiproliferative effects is not completely understood. We demonstrate that chronic and low doses of AEs treatment at sublethal concentrations suppress human breast cancer cell growth via a caspases-independent mechanism. Furthermore, AEs exposure induces a significant increase of senescence-associated β-galactosidase (SA-β-gal) staining and upregulation of tumour suppressor genes, p16(INK4a) and p21(Cip1/Waf1) in MDA-MB231 cells. AEs treatment leads to epigenetic alterations in cancer cells, modulating DNA hypomethylation and lysine acetylation levels in total proteins. Cell growth arrest correlates with increased reactive oxygen species (ROS) production in AEs treated breast cancer cells. Inhibition of ROS generation by N-acetylcysteine (NAC) attenuates the antiproliferative effect. These findings demonstrate that chronic AEs treatment inhibits breast cancer cell growth via the induction of premature senescence through epigenetic and ROS-mediated mechanisms. Our results suggest that artichoke polyphenols could be a promising dietary tool either in cancer chemoprevention or/and in cancer treatment as a nonconventional, adjuvant therapy.

No MeSH data available.


Related in: MedlinePlus

Chronic treatment of AEs induces cell senescence. MDA-MB231 cells were treated with low doses of AEs (10 and 30 μM) for 10 days and then analyzed for the SA-β-gal, senescence-associated β-galactosidase activity. The image shown is representative of at least three independent experiments. Scale bar: 50 μm. The senescent cells versus total cells were counted in random fields under an inverted microscope (20x) and the following data are the mean ± SD: C = 7.7 ± 0.5, 10 μM AEs = 31 ± 5.6, p = 0.0044∗∗, 30 μM AEs = 51 ± 6.6, p = 0.0005∗∗∗. Significant statistical differences are indicated by asterisks. Boxed area, regarding blue cells with a typical senescent flattened and enlarged morphology, is magnified (2x).
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fig2: Chronic treatment of AEs induces cell senescence. MDA-MB231 cells were treated with low doses of AEs (10 and 30 μM) for 10 days and then analyzed for the SA-β-gal, senescence-associated β-galactosidase activity. The image shown is representative of at least three independent experiments. Scale bar: 50 μm. The senescent cells versus total cells were counted in random fields under an inverted microscope (20x) and the following data are the mean ± SD: C = 7.7 ± 0.5, 10 μM AEs = 31 ± 5.6, p = 0.0044∗∗, 30 μM AEs = 51 ± 6.6, p = 0.0005∗∗∗. Significant statistical differences are indicated by asterisks. Boxed area, regarding blue cells with a typical senescent flattened and enlarged morphology, is magnified (2x).

Mentions: We investigated whether the cell growth arrest, in response to low doses of AEs, was caused by the induction of cellular senescence as demonstrated for chronic treatment of several polyphenols in cancer cells [39–42]. The detection of β-galactosidase positive cells reflects an increase in lysosomal mass in aging cells and it is widely regarded as a marker for senescence [43]. MDA-MB231 cells incubated without AEs showed no detectable SA-β-gal activity, whereas cells treated with 10 and 30 μM AEs revealed a marked X-gal staining in a dose-dependent manner after 10 days, as depicted in Figure 2. Most of the SA-β-gal positive cells showed an enlarged and flattened morphology with increased volume and granularity that were consistent with cellular senescence status, as shown in magnification area of Figure 2.


Long Term Exposure to Polyphenols of Artichoke (Cynara scolymus L.) Exerts Induction of Senescence Driven Growth Arrest in the MDA-MB231 Human Breast Cancer Cell Line.

Mileo AM, Di Venere D, Abbruzzese C, Miccadei S - Oxid Med Cell Longev (2015)

Chronic treatment of AEs induces cell senescence. MDA-MB231 cells were treated with low doses of AEs (10 and 30 μM) for 10 days and then analyzed for the SA-β-gal, senescence-associated β-galactosidase activity. The image shown is representative of at least three independent experiments. Scale bar: 50 μm. The senescent cells versus total cells were counted in random fields under an inverted microscope (20x) and the following data are the mean ± SD: C = 7.7 ± 0.5, 10 μM AEs = 31 ± 5.6, p = 0.0044∗∗, 30 μM AEs = 51 ± 6.6, p = 0.0005∗∗∗. Significant statistical differences are indicated by asterisks. Boxed area, regarding blue cells with a typical senescent flattened and enlarged morphology, is magnified (2x).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4477242&req=5

fig2: Chronic treatment of AEs induces cell senescence. MDA-MB231 cells were treated with low doses of AEs (10 and 30 μM) for 10 days and then analyzed for the SA-β-gal, senescence-associated β-galactosidase activity. The image shown is representative of at least three independent experiments. Scale bar: 50 μm. The senescent cells versus total cells were counted in random fields under an inverted microscope (20x) and the following data are the mean ± SD: C = 7.7 ± 0.5, 10 μM AEs = 31 ± 5.6, p = 0.0044∗∗, 30 μM AEs = 51 ± 6.6, p = 0.0005∗∗∗. Significant statistical differences are indicated by asterisks. Boxed area, regarding blue cells with a typical senescent flattened and enlarged morphology, is magnified (2x).
Mentions: We investigated whether the cell growth arrest, in response to low doses of AEs, was caused by the induction of cellular senescence as demonstrated for chronic treatment of several polyphenols in cancer cells [39–42]. The detection of β-galactosidase positive cells reflects an increase in lysosomal mass in aging cells and it is widely regarded as a marker for senescence [43]. MDA-MB231 cells incubated without AEs showed no detectable SA-β-gal activity, whereas cells treated with 10 and 30 μM AEs revealed a marked X-gal staining in a dose-dependent manner after 10 days, as depicted in Figure 2. Most of the SA-β-gal positive cells showed an enlarged and flattened morphology with increased volume and granularity that were consistent with cellular senescence status, as shown in magnification area of Figure 2.

Bottom Line: Furthermore, AEs exposure induces a significant increase of senescence-associated β-galactosidase (SA-β-gal) staining and upregulation of tumour suppressor genes, p16(INK4a) and p21(Cip1/Waf1) in MDA-MB231 cells.Inhibition of ROS generation by N-acetylcysteine (NAC) attenuates the antiproliferative effect.Our results suggest that artichoke polyphenols could be a promising dietary tool either in cancer chemoprevention or/and in cancer treatment as a nonconventional, adjuvant therapy.

View Article: PubMed Central - PubMed

Affiliation: Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy.

ABSTRACT
Polyphenolic extracts from the edible part of artichoke (Cynara scolymus L.) have been shown to be potential chemopreventive and anticancer dietary compounds. High doses of polyphenolic extracts (AEs) induce apoptosis and decrease the invasive potential of the human breast cancer cell line, MDA-MB231. However, the molecular mechanism underlying AEs antiproliferative effects is not completely understood. We demonstrate that chronic and low doses of AEs treatment at sublethal concentrations suppress human breast cancer cell growth via a caspases-independent mechanism. Furthermore, AEs exposure induces a significant increase of senescence-associated β-galactosidase (SA-β-gal) staining and upregulation of tumour suppressor genes, p16(INK4a) and p21(Cip1/Waf1) in MDA-MB231 cells. AEs treatment leads to epigenetic alterations in cancer cells, modulating DNA hypomethylation and lysine acetylation levels in total proteins. Cell growth arrest correlates with increased reactive oxygen species (ROS) production in AEs treated breast cancer cells. Inhibition of ROS generation by N-acetylcysteine (NAC) attenuates the antiproliferative effect. These findings demonstrate that chronic AEs treatment inhibits breast cancer cell growth via the induction of premature senescence through epigenetic and ROS-mediated mechanisms. Our results suggest that artichoke polyphenols could be a promising dietary tool either in cancer chemoprevention or/and in cancer treatment as a nonconventional, adjuvant therapy.

No MeSH data available.


Related in: MedlinePlus