Pro-Apoptotic Effect of Grape Seed Extract on MCF-7 Involves Transient Increase of Gap Junction Intercellular Communication and Cx43 Up-Regulation: A Mechanism of Chemoprevention

Abstract

Growing evidence suggests dietary antioxidants reduce the risk of several cancers. Grape seeds extracts (GSE) are a rich source of polyphenols known to have antioxidant, chemopreventive and anticancer properties. Herein, we investigated the in vitro effects and putative action mechanisms of a grape seed extract (GSE) on human breast cancer cells (MCF-7). The effects of GSE were evaluated on cell proliferation, apoptosis and gap-junction-mediated cell-cell communications (GJIC), as basal mechanism involved in the promotion stage of carcinogenesis. GSE (0.05–100 μg/mL) caused a significant dose- and time-dependent inhibition of MCF-7 viability and induced apoptotic cell death, as detected by Annexin-V/Propidium Iodide. Concurrently, GSE induced transient but significant enhancement of GJIC in non-communicating MCF-7 cells, as demonstrated by the scrape-loading/dye-transfer (SL/DT) assay and an early and dose-dependent re-localization of the connexin-43 (Cx43) proteins on plasma membranes, as assayed by immunocytochemistry. Finally, real-time-PCR has evidenced a significant increase in cx43 mRNA expression. The results support the hypothesis that the proliferation inhibition and pro-apoptotic effect of GSE against this breast cancer cell model are mediated by the GJIC improvement via re-localization of Cx43 proteins and up-regulation of cx43 gene, and provide further insight into the action mechanisms underlying the health-promoting action of dietary components.

Grape (Vitis vinifera L.) Seed Oil: A Functional Food from the Winemaking Industry

“…Of grape seed extracts, antioxidant and antimicrobial activities can be noted due to their phenolic components [ 53 , 54 , 55 ]. Additionally, some evidence shows that grape seed extract may provide anti-cancer chemoprevention [ 56 , 57 , 58 , 59 , 60 , 61 ] and cardio-protection [ 62 ]. Hao et al, studied the possible effect regarding hypertension and vascular remodeling to prevent stroke in rats [ 63 ].…”

Strategies for Reuse of Skins Separated From Grape Pomace as Ingredient of Functional Beverages

“…Grape by-products contain a variety of phytochemicals, especially phenols and flavonoids like anthocyanins, stilbenes, flavonols, and flavanols, and essential minerals (Cádiz-Gurrea et al, 2017 ; Tang et al, 2018 ). These bioactive molecules possess different biological activities such as antibacterial, antitumor, antioxidant, anti-inflammatory effects (Tomé-Carneiro et al, 2012 ; Xu et al, 2014 ; Vaisman and Niv, 2015 ; Ismail et al, 2016 ; Ferri et al, 2017 ; Iannone et al, 2017 ; Leone et al, 2019 ) which are effective in preventing chronic diseases (Li et al, 2017 ; Tang et al, 2017 ; Zhao et al, 2017 ; Meng et al, 2018 ).…”

Proanthocyanidins reduce cellular function in the most globally diagnosed cancers in vitro

“…GSEs were demonstrated to reduce carcinogenesis via gap junction-mediated cell–cell communication in MCF-7 breast cancer cells. Indeed, the pro-apoptotic properties of GSEs are facilitated by gap junction-mediated cell–cell communication via upregulated connexin cx43 gene expression ( Leone et al, 2019 ). Furthermore, the use of GSTs in vitro, in the context of HT-29 and LoVo cell cultures and in vivo, in the context of HT-29 tumor xenografts in athymic nude mice revealed that GSTs inhibit cancer cell growth (and volume increase), and upregulate Cip1/p21 expression ( Kaur et al, 2006b ).…”