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Carcinogenesis Advance Access published online on August 5, 2004
Carcinogenesis, doi:10.1093/carcin/bgh232
© 2004 by Oxford University Press
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Received April 8, 2004
Revised June 12, 2004
Accepted July 6, 2004

CANCER BIOLOGY

Anti-angiogenic activity of inositol hexaphosphate (IP6)

Ivana Vucenik 1, Antonino Passaniti 2, Michele I. Vitolo 3, Kwanchanit Tantivejkul 4, Paul Eggleton 5, AbulKalam M. Shamsuddin 4*

1 Department of Medical and Research Technology, University of Maryland School of Medicine, Baltimore, Maryland, USA; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA
2 Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA
3 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA
4 Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA
5 Peninsula Medical School, Universities of Exeter and Plymouth, England, UK; MRC Immunochemistry Unit, University of Oxford, England, UK

* To whom correspondence should be addressed. E-mail: shams{at}som.umaryland.edu.


  Abstract

A significant anti-cancer 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.

Keywords: phytic acid; vasostatin; Matrigel assay; capillary differentiation; VEGF.
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