Standardized Punica Granatum Pericarp Extract, Suppresses Tumor Proliferation and Angiogenesis in a Mouse Model of Melanoma: Possible Involvement of PPAR alpha and PPAR gamma Pathways

Abstract

Melanoma is a challenging disease to treat. Punica granatum L. has a potential anticancer effect. This study determined the antiproliferative and antiangiogenic potential of the extract from pomegranate pericarp (PPE) in melanoma. Melanoma cells (1 x 10(6)) were injected to C57BL6 mice subcutaneously. On 8th day, mice were randomly divided into 9 groups. Group 1 was considered as control and received distilled water. Groups 2 to 5 received 50, 100, 200 or 400 mg/kg of standardized PPE, orally. Group 6 received 400 mg/kg PPE and PPARy antagonist (T0070907, 5 mg/kg/day). Group 7 received 400 mg/kg PPE and PPAR-alpha antagonist (GW6471, 10 mg/kg/day). Groups 8 and 9 received PPAR antagonists alone. On the 16th day, mice were euthanized and the tumor samples were analyzed by immunohistochemistry staining for Ki-67 and CD31. Vascular endothelial growth factor (VEGF) plasma level was determined by ELISA. PPE at the doses of 50, 100, 200, and 400 mg/kg decreased tumor weight to 1.28, 1.03, 0.82, and 0.58 g. respectively, in comparison with 1.46 g in control group. Tumor volume reduced to 2.1, 1.7, 1.35 and 0.95 cm(3) at the mentioned doses, in comparison with 2.4 cm(3) in control group (P < 0.05 for all groups). VEGF, Ki-67 and CD31 were decreased dose dependently in the treatment groups (P < 0.05). PPARa and PPARy antagonists significantly reduced the extract effects (P < 0.05). It was concluded that PPE may have a potential implication in melanoma treatment through activation of PPARa and PPAR gamma receptors.