Polyphenol-induced Anti-inflammatory and Cytotoxic Activities in Breast and Colon Cancer: Potential Role of miRNA's in Cell Survival and Inflammation

Cancer is a major cause of death worldwide. Hence, there is a great need to develop novel therapeutic agents for the prevention and treatment of cancer in addition to conventional therapies. Dietary polyphenols are known to be effective in the prevention and treatment of several chronic diseases such as cancer, cardiovascular diseases, and diabetes. Particularly in carcinogenesis, polyphenols are known to suppress cancer growth, angiogenesis, and metastasis. Several studies have demonstrated that polyphenolics, ellagitannins, gallotannins, and chlorogenic acid from pomegranate, mango, and plum juice, respectively, are potent inhibitors of cancer cell proliferation and induce apoptosis and cell cycle arrest as well as decrease inflammation in vitro and vivo.

The therapeutically relevant compounds in pomegranate are pelagic acid, ellagitannins, flavonoids, and 3-glucosides/3,5-diglucosides of the anthocyanins delphinidin, cyanidin, and pelargonidin that exerted antioxidant, anti-inflammatory, and anticarcinogenic activities in vitro and vivo. Mango pulp extract contains gallotannins, gallic acid, galloyl glycosides, and flavonoids such as quercetin and kaempferol glycosides, which showed antioxidant, anti-inflammatory, and anticarcinogenic activities in vitro and in vivo. Chlorogenic acid and neo-chlorogenic acid are contained in plum juice and are also known to function as chemoprevention and chemotherapeutic agents.

The overall objective of this work was to investigate the underlying anti- inflammatory and cytotoxic mechanisms involving miR-27a-ZBTB10-Sp and miR-155- SHIP-1-PI3K axes, miR126-VCAM-1, miR126-PI3K/AKT-mTOR and miR143/PI3K/AKT/mTOR axes in polyphenol-mediated anti-inflammatory and anticarcinogenic activities in vitro and vivo.

Pomegranate and Mango polyphenols exhibited antioxidant, anti-inflammatory, anticarcinogenic, and antiproliferative activities in vitro and in vivo. Polyphenols inhibited cell proliferation of breast cancer cell line BT474 and suppressed tumor growth in athymic BALB/c nude mice with BT474 xenografts. Interactions of Pg with miR-27a- ZBTB10-Sp and miR-155-SHIP-1-PI3K axes and mango miR126/PI3K/AKT axis were identified. In addition, pomegranate and plum polyphenols exerted cytotoxic and anti- inflammatory effects in azoxymethane AOM-treated rats and colon cancer cells. Interactions of Pg with miR126/VCAM-1 and miR126/PI3K/AKT/mTOR axes and plum with miR143/PI3K/AKT/mTOR were identified as mechanisms that at least in part appear to be involved in the anti-inflammatory and antiproliferative activities of pomegranate and plum polyphenolics.

The presented research was conducted in order to understand the efficacy of polyphenols present in pomegranate, mango and plum and their underlying molecular mechanisms in different cancer models.