Ellagic Acid Normalizes Mitochondrial Outer Membrane Permeabilization and Attenuates Inflammation-Mediated Cell Proliferation in Experimental Liver Cancer

Abstract

Despite great advances in our understanding of the molecular causes of liver cancer, significant gaps still remain in our knowledge of the disease pathogenesis and development of effective strategies for early diagnosis and treatment. The present study was conducted to evaluate the chemopreventive activity of ellagic acid (EA) against experimental liver cancer in rats. This is the first report that implies a possible role of EA in controlling liver cancer through activation of mitochondrial outer membrane permeability via activating proteins such as Bax, bcl-2, cyt-C, and caspase-9, which play important roles in apoptosis. Downregulation of NF-κB, cyclin D1, cyclin E1, matrix metalloproteinases (MMP)-2, MMP-9, and proliferating cell nuclear antigen (PCNA) were noted in EA-treated experimental rats and controlled inflammation mediated liver cancer when compared to the diethylnitrosamine (DEN)-induced group. Transmission electron microscopy (TEM) analysis of the livers of experimental rats demonstrated that EA treatment renovated its internal architecture. Overall, these results demonstrate the value of molecular approaches in identifying the potential role of EA as an effective chemopreventive agent.

Natural Polyphenols for Prevention and Treatment of Cancer

“…Ellagic acid (50–200 μM) exerted anti-proliferative and pro-apoptotic effects in colon cancer cell lines in a concentration dependent manner [144]. Besides, in a chemical-induced liver cancer rat model, oral administration of ellagic acid (30 mg/kg/day) normalized the permeability of mitochondrial outer membrane and alleviated inflammation-mediated cancer cell proliferation [145]. Ellagic acid (10–40 μg/mL) also showed growth inhibitory effects on MCF-7 breast cancer cells, which was accompanied by G 0 /G 1 cell cycle arrest.…”

Ellagic acid: Pharmacological activities and molecular mechanisms involved in liver protection

“…Recently, a couple of studies were published supporting that EA could be a promising agent against chemical-induced HCC. Srigopalram et al [306] demonstrated that EA restrains abnormal proliferation of hepatocytes by the stimulation of apoptosis and regulating the permeabilization of the mitochondrial outer membrane. Apoptosis is a type of cell death tightly controlled by extrinsic stimuli through cell surface death receptors or by intrinsic stimuli via the mitochondrial signaling pathway, giving as a result the activation of proteases termed caspases that cleave a variety of cellular targets, resulting in morphological changes, mitochondrial permeability transition pore (mPTP) opening, release of cytochrome c, degradation of genomic DNA, and thereby, phagocytic removal of the apoptotic cell [307,308].…”

Therapeutic Potential of Dietary Phenolic Acids

“…Similarly, EA downregulates the expression of oncogene Myc and upregulates tumor suppressor gene TGF- β in lymphoma bearing mice. EA also exerts apoptosis through targeting PI3K/Akt kinases that in turn resulted in attenuation of its downstream Bcl-2 family proteins in 1,2-dimethyl hydrazine- (DMH-) induced rat colon carcinogenesis [ 45 ]. EA could stimulate the apoptosis by decreasing NF- κ B activity, thus activating the mitochondrial death pathway associated with caspase 3 activation and cytochrome C release [ 46 ].…”