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. 2018 Jan;15(1):908-916.
doi: 10.3892/ol.2017.7434. Epub 2017 Nov 17.

Inhibition of breast cancer cell survival by Xanthohumol via modulation of the Notch signaling pathway in vivo and in vitro

Zhihong Sun  1 , Cheng Zhou  1 , Feng Liu  1 , Wenchao Zhang  1 , Jing Chen  1 , Yanlong Pan  1 , Lianqing Ma  2 , Qimin Liu  2 , Yuping Du  1 , Jinbo Yang  1 , Qin Wang  1
Affiliations

Inhibition of breast cancer cell survival by Xanthohumol via modulation of the Notch signaling pathway in vivo and in vitro

Zhihong Sun et al. Oncol Lett. 2018 Jan.

Abstract

Natural compounds derived from plants have been an important source of numerous clinically useful anticancer agents VSports手机版. Nevertheless, limited studies indicate that xanthohumol (XN), a major prenylated flavonoid in hop plants (Humulus lupulus), may possess anticarcinogenic properties. The purpose of the present study was to clarify the antitumorigenic effects and the underlying mechanism of XN on breast cancer in vivo and in vitro. A 4T1 breast tumor mouse model was used in the present study to investigate XN suppression of tumor growth as detected by tumorigenicity assays in vivo. In addition, in vitro studies revealed that XN significantly decreased cell viability, induced G0/G1 cell cycle arrest and apoptosis in MCF-7 and MDA-MB-231 cells, as confirmed by an MTT assay, flow cytometry and western blot analysis, indicating anticarcinogenic activity of XN against breast cancer. Furthermore, immunohistochemistry was performed to confirm the inactivation of the Notch signaling pathway, Notch 1 and Ki-67, in vivo; consistently, XN caused decreased activation of the Notch signaling pathway and apoptotic regulators B-cell lymphoma-2 (Bcl-2), Bcl-extra large and caspase 3, as determined by western blot analysis in vitro. This study suggests that XN may potentially be useful as a chemopreventive agent during breast hyperplasia and carcinogenesis, acting via the regulation of Notch associated apoptotic regulators in vivo and in vitro. .

Keywords: Notch signaling pathway; apoptosis; breast cancer; cell cycle; migration; xanthohumol. V体育安卓版.

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V体育2025版 - Figures

Figure 1.
Figure 1.
XN inhibited Notch1 activity. (A) XN inhibited Notch1-dependent luciferase activity. Luciferase data were normalized to β-galactosidase and are presented as the means ± SD. *P<0.05, **P<0.01 vs. control. (B) Notch 1 and Hes1 protein expression levels were detected by western blotting. (C) XN inhibited Notch1-specific downstream gene Hes1 and Hey1 mRNA expression levels. DLL-4; anti-delta-like 4; DAPT, Duration of Dual Antiplatelet Therapy; Ctrl, control; XN, xanthohumol; Hes1, hairy enhancer of split 1; hey1, Hes related family BHLH transcription factor with YRPW motif 1.
Figure 2.
Figure 2.
XN inhibited breast cancer cell proliferation in a dose- and time-dependent manner. (A) h-TERT-BJ, MCF-10A, MCF-7 and MDA-MB-231 were plated equally (six replicates) and treated with XN. MTT assays were performed daily for two days. DMSO was a vehicle control. (B) MDA-MB-231 and MCF-7 cells were treated with 20 µM XN for 24–72 h and visualized by light microscopy. (C) The c-Myc and survivin protein expression levels were detected by western blotting. (D) The Boyden chamber transwell assay demonstrated MDA-MB-231 cell migration. MCF-7 and MDA-MB-231 cells were treated with XN (data are presented as the mean ± SEM of three independent experiments). (E) Quantification of migrated MDA-MB-231 cells. Data are presented as the mean ± SEM of three independent experiments. *P<0.05, **P<0.01 vs. control. (F) EGFR and MIF expression levels were determined by western blot analysis. SEM; standard error of the mean; DMSO, dimethyl sulfoxide; EGFR, epidermal growth factor receptor; MIF, tumor metastasis-associated protein; CDK4, cyclin-dependent kinase 4; DAPT, Duration of Dual Antiplatelet Therapy; XN, xanthohumol; Ctrl, control.
Figure 3.
Figure 3.
XN arrests the cell cycle in the G0/G1 phase. (A) XN regulated cell cycle protein expression levels were detected by western blotting. (B) MCF-7 and MDA-MB-231 cells were harvested for cell cycle analysis using PI staining. PI, propidium iodide; CDK4, cyclin-dependent kinase 4; DAPT, Duration of Dual Antiplatelet Therapy; Ctrl, control; XN, xanthohumol.
Figure 4.
Figure 4.
XN promote apoptosis of breast cells. (A) MCF-7 and MDA-MB-231 cells were harvested for apoptotic analysis using Annexin V-FITC staining. (B) Quantification of apoptosis. Data are presented as the mean ± SD error of the mean of three independent experiments. (C) Apoptosis associated proteins Bcl-2, Bcl-xL and caspase-3 and cleaved PARP were analyzed by western blotting. GAPDH was used as the control. FITC, fluorescein isothiocyanate; FITC-A, FITC-annexin; Ctrl, control; XN, xanthohumol; DAPT, Duration of Dual Antiplatelet Therapy; PI-A, propidium iodide annexin; Bcl-2, B cell lymphoma-2; Bcl-xL, B cell lymphoma extra 1; PARP, poly (ADP-ribose) polymerase.
Figure 5.
Figure 5.
XN inhibited tumor growth in vivo. (A) Total average mouse weights. 4T1 cells (1×105) were subcutaneously grafted to 8-week-old BALB/c mice. (B) Images of the tumors. (C) Tumor sizes of BALB/c mice treated with the control vehicle or XN as indicated. (D) Immunohistochemistry analysis for protein expression (×10). (E) Hematoxylin and eosin staining (×10 and ×40) revealed the tumor tissues of mice. Ctrl, control; XN, xanthohumol.
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