Cancer:
Pancreatic, prostate, ovarian, breast, bladder, lymphoma, oral., melanoma
Action: Anti-cancer, induces apoptosis, promoted ROS and Ca2+ productions
Ellagic acid (EA) is a polyphenol compound widely found in fruits such as berries, walnuts, pecans, pomegranate, cranberries, and longan. It is well known to have a free radical scavenging activity and has been approved in Japan as an 'existing food additive' for anti-oxidative purposes (HHLW, 1996). In vitro evidence revealed that 100µM EA represented little toxic effect on human normal cells (Losso et al., 2004; Larrosa et al., 2006). A subchronic toxicity study further demonstrated that orally feeding EA (9.4, 19.1, 39.1g/kg b.w., resp.) could not induce mortality or treatment-related clinical signs throughout the experimental period on F344 rats (Tasaki et al., 2008), indicating the low toxicity of EA to mammalians. Furthermore, EA exhibits potent anti-cancer and anti-carcinogenesis activities towards breast, colorectal., oral., prostate (Losso et al., 2004; Larrosa et al., 2006; Malik et al., 2011), pancreatic (Edderkaoui et al., 2008), bladder (Li et al., 2005), neuroblastoma (Fjaeraa et al., 2009), melanoma (Kim et al., 2009), and lymphoma cells (Mishra et al., 2011).
Pancreatic Cancer
Edderkaoui et al. (2008) show that ellagic acid, a polyphenolic compound in fruits and berries, at concentrations 10 to 50 mmol/L stimulates apoptosis in human pancreatic adenocarcinoma cells. Ellagic acid stimulates the mitochondrial pathway of apoptosis associated with mitochondrial depolarization, cytochrome C release, and the downstream caspase activation. Ellagic acid does not directly affect mitochondria. Ellagic acid dose-dependently decreased NF-kappa B binding activity.
Furthermore, inhibition of NF-kappa B activity using IkB wild type plasmid prevented the effect of ellagic acid on apoptosis.
Pancreatic Cancer (PANC-1) cells were injected subcutaneously into Balb c nude mice, and tumor-bearing mice were treated with ellagic acid (EA). Treatment of PANC-1 xenografted mice with EA resulted in significant inhibition in tumor growth which was associated with suppression of cell proliferation and caspase-3 activation, and induction of PARP cleavage. EA also reversed epithelial to mesenchymal transition by up-regulating E-cadherin and inhibiting the expression of Snail, MMP-2 and MMP-9.
These data suggest that EA can inhibit pancreatic cancer growth, angiogenesis and metastasis by suppressing Akt, Shh and Notch pathways. In view of the fact that EA could effectively inhibit human pancreatic cancer growth by suppressing Akt, Shh and Notch pathways, our findings suggest that the use of EA would be beneficial for the management of pancreatic cancer (Zhao et al., 2013).
Ovarian Cancer
Ovarian carcinoma ES-2 and PA-1 cells were treated with EA (10~100 µ M) and assessed for viability, cell-cycle, apoptosis, anoikis, autophagy, and chemosensitivity to doxorubicin and their molecular mechanisms. EA inhibited cell proliferation in a dose- and time-dependent manner by arresting both cell lines at the G1 phase of the cell-cycle, which were from elevating p53 and Cip1/p21 and decreasing cyclin D1 and E levels. EA also induced caspase-3-mediated apoptosis by increasing the Bax : Bcl-2 ratio and restored anoikis in both cell lines.
The enhancement of apoptosis and/or inhibition of autophagy in these cells by EA assisted the chemotherapy efficacy. The results indicated that EA is a potential novel chemoprevention and treatment assistant agent for human ovarian carcinoma Chung et al., 2013).
Prostate Cancer; AR+
In the present study, Pitchakarn et al. (2013) investigated anti-invasive effects of ellagic acid (EA) in androgen-independent human (PC-3) and rat (PLS10) prostate cancer cell lines in vitro. The results indicated that non-toxic concentrations of EA significantly inhibited the motility and invasion of cells examined in migration and invasion assays. They found that EA significantly reduced proteolytic activity of collagenase/gelatinase secreted from the PLS-10 cell line. Collagenase IV activity was also concentration-dependently inhibited by EA. These results demonstrated that EA has an ability to inhibit invasive potential of prostate cancer cells through action on protease activity.
Breast Cancer
The role of estrogen (E2) in regulation of cell proliferation and breast carcinogenesis is well-known. Recent reports have associated several miRNAs with estrogen receptors in breast cancers. Investigation of the regulatory role of miRNAs is critical for understanding the effect of E2 in human breast cancer, as well as developing strategies for cancer chemoprevention.
In this study Munagala et al. (2013) used the well-established ACI rat model that develops mammary tumors upon E2 exposure and identified a 'signature' of 33 significantly modulated miRNAs during the process of mammary tumorigenesis. Several of these miRNAs were altered as early as 3 weeks after initial E2 treatment and their modulation persisted throughout the mammary carcinogenesis process, suggesting that these molecular changes are early events. This is the first systematic study examining the changes in miRNA expression associated with E2 treatment in ACI rats as early as 3weeks until tumor time point. The effect of a chemo-preventive agent, ellagic acid in reversing miRNAs modulated during E2-mediated mammary tumorigenesis is also established. These observations provide mechanistic insights into the new molecular events behind the chemo-preventive action of ellagic acid and treatment of breast cancer.
Bladder Cancer
To investigate the effects of ellagic acid on the growth inhibition of TSGH8301 human bladder cancer cells in vitro, cells were incubated with various doses of ellagic acid for different time periods. Results indicated that ellagic acid induced morphological changes, decreased the percentage of viable cells through the induction of G0/G1 phase arrest and apoptosis, and also showed that ellagic acid promoted ROS and Ca2+ productions and decreased the level of ΔΨm and promoted activities of caspase-9 and -3.
On the basis of these observations, Ho et al (2013) suggest that ellagic acid induced cytotoxic effects for causing a decrease in the percentage of viable cells via G0/G1 phase arrest and induction of apoptosis in TSGH8301 cells.
Lymphoma
Protein Kinase C (PKC) isozymes are key components involved in cell proliferation and their over activation leads to abnormal tumor growth. PKC follows signaling pathway by activation of downstream gene NF-kB and early transcription factor c-Myc. Over activation of NF-kB and c-Myc gene are also linked with unregulated proliferation of cancer cells.
Therefore any agent which can inhibit the activation of Protein kinase C, NF-kB and c-Myc may be useful in reducing cancer progression. The role of ellagic acid was tested in regulation of tumor suppressor gene Transforming growth factor-β1 (TGF-β1). DL mice were treated with three different doses (40, 60 and 80 mg/kg body weight) of ellagic acid. Ascites cells of mice were used for the experiments. Ellagic acid administration to DL mice decreased oxidative stress by reducing lipid peroxidation.
The anti-carcinogenic action of ellagic acid was also confirmed by up-regulation of TGF-β1 and down-regulation of c-Myc. Lymphoma prevention by ellagic acid is further supported by decrease in cell proliferation, cell viability, ascites fluid accumulation and increase in life span of DL mice. All these findings suggest that ellagic acid prevents the cancer progression by down- regulation of PKC signaling pathway leading to cell proliferation (Mishra et al., 2013).
References
Zhao M, Tang SN, Marsh JL, et al. (2013). Ellagic acid inhibits human pancreatic cancer growth in Balb c nude mice. Cancer Letters, 337(2):210–217