Carcinogenesis Advance Access originally published online on August 5, 2004
Carcinogenesis 2004 25(11):2115-2123; doi:10.1093/carcin/bgh232
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Carcinogenesis vol.25 no.11 © Oxford University Press 2004; all rights reserved.
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Anti-angiogenic activity of inositol hexaphosphate (IP6)
1 Department of Medical and Research Technology, 2 Department of Pathology and 3 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA and 4 Peninsula Medical School, Universities of Exeter and Plymouth and MRC Immunochemistry Unit, University of Oxford, Oxford, UK
5 To whom correspondence should be addressed Email: shams{at}som.umaryland.edu
A significant anticancer activity of the naturally occurring carbohydrate inositol hexaphosphate (IP6) has been reported against numerous cancer models. Since tumors require angiogenesis for growth and metastasis, we hypothesize that IP6 reduces tumor growth by inhibiting angiogenesis. Because angiogenesis depends on the interaction between endothelial and tumor cells, we investigated the effect of IP6 on both. IP6 inhibited the proliferation and induced the differentiation of endothelial cells in vitro; the growth of bovine aortic endothelial cells (BAECs) evaluated by MTT proliferation assay was inhibited in a dose-dependent manner (IC50 = 0.74 mM). The combination of IP6 and vasostatin, a calreticulin fragment with anti-angiogenic activity, was synergistically superior in growth inhibition than either compound. IP6 inhibited human umbilical vein endothelial cell (HUVEC) tube formation (in vitro capillary differentiation) on a reconstituted extracellular matrix, Matrigel, and disrupted pre-formed tubes. IP6 significantly reduced basic fibroblast growth factor (bFGF)-induced vessel formation (P < 0.01) in vivo in Matrigel plug assay. Exposure of HepG2, a human hepatoma cell line, to IP6 for 8 h, resulted in a dose-dependent decrease in the mRNA levels of vascular endothelial growth factor (VEGF), as assessed by RT–PCR. IP6 treatment of HepG2 cells for 24 h also significantly reduced the VEGF protein levels in conditioned medium, in a concentration-dependent manner (P = 0.012). Thus, IP6 has an inhibitory effect on induced angiogenesis.
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