Azione citodifferenziante ed antitumorale dell'acido ellagico

Abstract

Il lavoro ha lo scopo di valutare l'effetto citodifferenziante ed antitumorale dell'acido ellagico in tre diverse linee cellulari prostatiche a diverso grado di invasivita' (DU145, LnCap, BPH1). I risultati della Cromogranina A e della P75 NGRF, ottenuti mediante immunofluorescenza, evidenziano un'azione citodifferenziante dell'acido ellagico in maniera dose dipendente. Inoltre i risultati dimostrano come l'acido ellagico abbia la capacita' di ridurre, in maniera dose dipendente, sia l'espressione di alcune proteine coinvolte nella regolazione della proliferazione cellulare (pRb, DNMT-1, P21, P53, Caspasi 3). L'utilizzo di functional food riduce il rischio di molte patologie; questo e' il messaggio che bisogna trasmettere alle generazioni future.

Ellagic acid (2,3,7,8-tetrahydroxy[1]-benzopyrano[5,4,3-cde][1]benzopyran-5,10-dione) is a phenolic compound present in fruits and nuts, such as raspberries, strawberries, walnuts, longan seed, mango kernel and pomegranate. The fruit of the Punica granatum (pomegranate) contains hundreds of phytochemicals and its extracts have recently been shown to exhibit antioxidant properties, thought to be due to the action of ellagic acid, the main polyphenol in pomegranate. Pomegranate soluble polyphenols contain hydrolyzable tannins such as the ellagitannin punicalagin, gallic and ellagic acids, as well as anthocyanins and catechins. There is now increasing interest in the in vivo protective effects of natural antioxidants contained in dietary plants against oxidative damage caused by free radical species. Oxidative stress was involved as a causative agent in a number of human diseases including cancer and epidemiological data suggested that consumption of fruits and vegetables might be associated with a lower incidence of cancer. In view of these considerations, in this study we investigated the effects of ellagic acid on LnCaP and DU145 prostatic cancer cell lines. BPH-1 cells were employed as non malignant cells. Cytodifferentiation of malignant/premalignant cells into more mature or normal-like cells and apoptosis during multistep carcinogenesis are theoretically suitable in cancer therapy. Thus, compounds capable of inducing differentiation or apoptosis are candidate chemopreventive and /or chemotherapeutic agents. In this study, the evaluation of chromogranim A levels was used as a marker of neuroendocrine differentiation. In order to elucidate mechanisms involved in anticancer activity of ellagic acid, we analyze by western blotting analysis the expression of different proteins (p75NGFR, DNA-metiltransferasi-1, pRb, p53, p21 e caspasi-3) involved in cells growth and apoptosis. In addition, LDH release and ROS levels were evaluated. Our data evidence the ability of ellagic acid to reduce cell proliferation, to induce apoptosis and cytodifferentiation. In addition, our results, provide morphological and biochemical evidence suggesting that ellagic acid is able to revert LnCap and DU145 cells from the neuroendocrine proliferating state to normal-like un-proliferating state. Then, our study to furtherly support the growing body of data suggesting the bioactivities of natural compounds and their potential impact on cancer therapy and on human health.