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Delphinidin, one of the main anthocyanidins, has potent anti-cancer properties. In this study, we investigated the effect of delphinidin on 1-methyl-1-nitrosourea (MNU)-induced breast carcinogenesis on rats and the mechanism of delphinidin via negative regulation of the HOTAIR/microRNA-34a axis. We found administration of delphinidin could effectively suppress MNU-induced mammal breast carcinogenesis. Delphinidin downregulated the level of HOTAIR and upregulated miR-34a in breast carcinogenesis. Western blot analysis confirmed that delphinidin treatment can significantly decrease the expression of β-catenin, glycogen synthase kinase-3β (Gsk3β), c-Myc, cyclin-D1, and matrix metalloproteinase-7(MMP-7) expression in breast cancer cells, and inhibition of miR-34a significantly reduced the effect of delphinidin on c-Myc, cyclin-D1, and MMP-7. HOTAIR overexpression also blocked the effect of delphinidin on miR-34a and the Wnt/β-catenin signaling pathway in MDA-MB-231 cells. RNA immunoprecipitation (RIP) assay and chromatin immunoprecipitation (ChIP) assay results showed that delphinidin upregulated miR-34a by inhibiting HOTAIR, coupled with enhancement of the zeste homolog 2 (EZH2) and histone H3 Lys27 trimethylation (H3K27me3). This study indicated that delphinidin may potentially suppress breast carcinogenesis and exert its anti-cancer effect through the HOTAIR/miR-34a axis. These findings provided new evidence for the use of delphinidin in preventing breast carcinogenesis., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: We have previously demonstrated the anticancer effect of anthocyanins. In this study, we explored the biological activities of delphinidin, the most common of the anthocyanidin monomers, that were related to autophagy in HER-2 positive breast cancer MDA-MB-453 and BT474 cells., Methods: The effects of various doses of delphinidin on the proliferation and apoptosis of MDA-MB-453 and BT474 cells were analysed. Autophagy was identified as a critical factor that influenced chemotherapy, and the autophagic mechanism in delphinidin-treated cells was investigated. The autophagy inhibitors, 3-MA and BA1, were used to analyse the effects of autophagy inhibition., Results: Delphinidin inhibited proliferation, promoted apoptosis, and induced autophagy in MDA-MB-453 and BT474 cells in a dose-dependent manner. The inhibition of autophagy enhanced the delphinidin-induced apoptosis and antiproliferative effect in both HER-2 positive breast cancer cells. In addition, delphinidin induced autophagy via suppression of the mTOR signalling pathway and activation of the AMPK signalling pathway in HER-2 positive breast cancer cells., Conclusions: Collectively, the results showed that delphinidin induced apoptosis and autophagy in HER-2 positive breast cancer cells and that autophagy was induced via the mTOR and AMPK signalling pathways. The suppression of autophagy promoted the anticancer effects of delphinidin.

Background: The long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) plays a crucial role in cancer progression, which is regulated by the interferon regulatory factor-1 (IRF1) and up-streaming Akt activation. The present study evaluated the chemopreventive effects of delphinidin-3-glucoside (Dp), a major anthocyanin present in pigmented fruits and vegetables, on breast carcinogenesis, and investigate the role of the Akt/HOTAIR signaling pathway., Methods: Human breast epithelial cells MCF10A were treated with carcinogens (NNK and B[a]P) or co-treated with carcinogens plus Dp for 30 days. Then, the cancer-associated properties of the treated cells were evaluated to assess the carcinogenesis and the effects of Dp. HOTAIR levels were detected by qRT-PCR. The proteins expression was measured by western blots, immunofluorescence and immunohistochemistry. Xenografted tumors were made by implanting breast cancer cells MDA-MB-231-Luc-GFP in athymic mice. ChIP-qPCR analysis was used to detect the IRF1 binding to the HOTAIR promoter., Results: Carcinogens treatment induces apparent carcinogenic transformation in MCF10A cells including reduced dependence on growth factors, anchorage-independent cell growth and aberrant wound-healing ability, which is effectively suppressed by Dp co-treatment. The level of HOTAIR significantly increases in a time-dependent manner during chronic breast carcinogenesis. Dp treatment down-regulates HOTAIR expression in breast carcinogenesis and breast cancer cells. Furthermore, Dp administration inhibits the growth of xenografted breast tumors in athymic mice, and decreases HOTAIR in vivo. Further studies showed that Dp represses Akt activation, promotes IRF1 expression and increases IRF1 binding to the HOTAIR promoter. Silence of IRF1 expression via transfecting cells with IRF1 siRNAs significantly reduced the effects of Dp on HOTAIR, resulting in decreased cytotoxic effects of Dp on breast cancer cells., Conclusions: These data suggest the effective chemopreventive effect of Dp on breast carcinogenesis, in which down-regulation of HOTAIR plays a critical role.

Scope: Oxidized LDL (oxLDL) induced vascular endothelial cell injury is a key event in the pathogenesis of atherosclerosis (AS). In our previous studies, we showed that delphinidin-3-glucoside (Dp), a natural anthocyanin, attenuated oxLDL-induced injury in human umbilical vein endothelial cells (HUVECs), indicating its potential role in preventing AS. However, the involved mechanism is not fully understood., Methods and Results: Via methyl thiazolyl tetrazolium and flow cytometry assay, we found that Dp-attenuated oxLDL-induced cell viability decrease and apoptosis in HUVECs. Depending on confocal microscopy, transmission electron microscopy, and Western blot assay, we found that Dp-induced autophagy in HUVECs, whereas suppression of autophagy significantly abolished the protective role of Dp against oxLDL-induced endothelial cell injury. Furthermore, Dp upregulated sirtuin 1 (SIRT1) expression and SIRT1 knockdown notably suppressed Dp-induced autophagy in HUVECs. Dp also increased the expression of phosphorylated adenosine monophosphate-activated protein kinase, while adenosine monophosphate-activated protein kinase (AMPK) knockdown remarkably abolished Dp-induced SIRT1 expression and subsequent autophagy., Conclusion: Our data suggested that Dp protected HUVECs against oxLDL-induced injury by inducing autophagy via the adenosine monophosphate-activated protein kinase/SIRT1 signaling pathway. This new finding might shed light to the prevention and therapy of AS., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Anthocyanins are a ubiquitous group of water-soluble plant pigments of the flavonoid family, with anticancer property through HER-2 signaling pathway. Nowadays, molecular docking plays an important role in exposing the active sites and obtaining the bioactive conformation involving protein-ligand interactions. According to the crystal structure of HER-2 kinase domain and 12 main antitumor compounds of anthocyanins as well as ATP, a molecular docking study was performed by MVD program. All 12 compounds could bind to the same cavity of HER-2 kinase domain by high affinity (MolDock Score < -105 kJ/mol for anthocyanidins, < -130 kJ/mol for anthocyanidins-glc), where hydrophobic force and hydrogen bond played key roles. Additionally, this cavity overlapped with ATP binding (MolDock Score = -161 kJ/mol) domain; the binding of anthocyanins presumably interfered the H bond formation between ATP and HER-2. These results indicate that anthocyanins may competitively bind to ATP binding site in HER-2 kinase domain by suppressing HER-2 activation and downstream signaling cascade. This may provide useful theoretical instruction for the molecular mechanism of HER-2 kinase activity inhibition by anthocyanins in cancer prevention and treatment.

Background: Studies have suggested the chemopreventive effects of flavonoids on carcinogenesis. Yet numbers of epidemiologic studies assessing dietary flavonoids and breast cancer risk have yielded inconsistent results. The association between flavonoids, flavonoid subclasses (flavonols, flavan-3-ols, etc.) and the risk of breast cancer lacks systematic analysis. Objective: We aimed to examine the association between flavonoids, each flavonoid subclass (except isoflavones) and the risk of breast cancer by conducting a meta-analysis. Design:We searched for all relevant studies with a prospective cohort or case-control study design published before July 1st, 2012, using Cochrane library, MEDLINE, EMBASE and PUBMED. Summary relative risks (RR) were calculated using fixed-or random-effects models. All analyses were performed using STATA version 10.0. Results:Twelve studies were included, involving 9 513 cases and 181 906 controls, six of which were prospective cohort studies, and six were case-control studies. We calculated the summary RRs of breast cancer risk for the highest vs lowest categories of each flavonoid subclass respectively. The risk of breast cancer significantly decreased in women with high intake of flavonols (RR = 0.88, 95% CI 0.80-0.98) and flavones (RR = 0.83, 95% CI: 0.76-0.91) compared with that in those with low intake of flavonols and flavones. However, no significant association of flavan-3-ols (RR = 0.93, 95% CI: 0.84-1.02), flavanones (summary RR = 0.95, 95% CI: 0.88-1.03), anthocyanins (summary RR = 0.97, 95% CI: 0.87-1.08) or total flavonoids (summary RR = 0.98, 95% CI: 0.86-1.12) intake with breast cancer risk was observed. Furthermore, summary RRs of 3 case-control studies stratified by menopausal status suggested flavonols, flavones or flavan-3-ols intake is associated with a significant reduced risk of breast cancer in post-menopausal while not in pre-menopausal women. Conclusions: The present study suggests the intake of flavonols and flavones, but not other flavonoid subclasses or total flavonoids, is associated with a decreased risk of breast cancer, especially among post-menopausal women. [ABSTRACT FROM AUTHOR]