Penta-O-galloyl-beta-d-glucose suppresses tumor growth via inhibition of angiogenesis and stimulation of apoptosis: roles of cyclooxygenase-2 and mitogen-activated protein kinase pathways

arcinogenesis (August 2005) 26 (8): 1436-1445. doi: 10.1093/carcin/bgi097
Recent studies have revealed that 1,2,3,4,6-penta-O-galloyl-beta-d-glucose (PGG) from Punica granatum, (pomegranate) or in Rhus typhina has anti-tumorigenic activity in vitro. In the present work, we evaluated the in vitro and in vivo antiangiogenic and antitumor activities of PGG and examined its molecular mechanisms. PGG significantly inhibited the proliferation and tube formation in basic fibroblast growth factor (bFGF)-treated human umbilical vein endothelial cells (HUVECs) at non-cytotoxic concentrations.
PGG effectively disrupted the bFGF-induced neo-vascularization in chick chorioallantoic membrane (CAM) and in Matrigel plugs in the mice. When mice were intraperitoneally injected, PGG also significantly inhibited tumor angiogenesis induced by Lewis lung carcinoma (LLC) and the growth of LLC by 57 and 91% of control tumor weight at 4 and 20 mg/kg, respectively. Immunohistochemical analysis revealed decreased microvessel density, decreased expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), reduced tumor cell proliferation and increased tumor cell apoptosis. Similarly, PGG significantly attenuated the expression of COX-2 and VEGF and reduced the secretion of VEGF and prostaglandin E2 in bFGF-treated HUVECs.
Furthermore, the COX-2 inhibitor NS398 significantly inhibited tube formation and neo-vascularization in CAM, supporting the role of COX-2 in PGG inhibition of angiogenesis. PGG diminished the phosphorylation of extracellular signal regulated kinase 1/2, Jun NH2-terminal kinase and activated phospho-p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner in bFGF-treated HUVECs. In addition, p38 inhibitor SB203580 abolished the downregulation of COX-2, VEGF and the antiproliferative activity by PGG. Taken together, our data demonstrate that PGG exerts antitumor activity primarily via inhibition of angiogenesis through COX-2 and MAPK- dependent pathways.

Cancer Chemoprevention by Pomegranate: Laboratory and Clinical Evidence

Pomegranate fruit from the tree Punica granatum has been dubbed as the “nature’s power fruit.” Dating back to Biblical times, the tree itself is attributed to possess extraordinary medicinal properties. The geographical distribution of the tree, being native to the Middle East and some Asian countries, is generally attributed to a lack of interest in its medicinal properties by many western scientists. However, the unique biochemical composition of the pomegranate fruit being rich in antioxidant tannins and flavonoids has recently drawn attention of many investigators to study its exceptional healing qualities. Recent research has shown that pomegranate extracts selectively inhibit the growth of breast, prostate, colon and lung cancer cells in culture. In preclinical animal studies, oral consumption of pomegranate extract inhibited growth of lung, skin, colon and prostate tumors. An initial phase II clinical trial of pomegranate juice in patients with prostate cancer reported significant prolongation of prostate specific antigen doubling time. This review focuses on recent investigations into the effects of pomegranate fruit on cancer. Antioxidant activities of freeze-dried preparations of pomegranate and its 3 major anthocyanidins; delphinidin, cyanidin, and pelargonidin. It is interesting to note that many studies have observed the extract or the juice to be more beneficial compared to the individual or purified ingredient. This suggests the existence of a chemical synergy when using an extract.
Vaqar Mustafa Adhami, Naghma Khan, and Hasan Mukhtar. Nutrition and Cancer, 61(6) Pp. 811–5 DOI: 10.1080/01635580903285064

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