Multifocal Angiostatic Therapy: An Update

Abstract

Multifocal angiostatic therapy (MAT) is a strategy that seeks to impede cancer-induced angiogenesis by addressing multiple targets that regulate the angiogenic capacity of a cancer and/or the angiogenic responsiveness of endothelial cells, using measures that are preferentially, but not exclusively, nutraceutical. A prototype of such a regimen has been proposed previously, composed of green tea polyphenols, fish oil, selenium, and high-dose glycine, complementing a low-fat vegan diet, exercise training, and the copper-sequestering drug tetrathiomolybdate (TM). A review of more recent evidence suggests additional agents that could appropriately be included in this regimen and clarifies to some extent the mechanisms of action of its constituents. Diindolylmethane, a widely available crucifera-derived nutraceutical, has inhibited cancer growth in several mouse xenograft models; this effect may be largely attributable to an angiostatic action, as concentrations as low as 5 to 10 µM inhibit proliferation, migration, and tube-forming capacity of human endothelial cells in vitro, and a parenteral dose of 5 mg/kg markedly impairs matrigel angiogenesis in mice. Silymarin/silbinin, which has slowed the growth of human xenografts in a number of studies, suppresses the proliferation, migration, and tube-forming capacity of endothelial cells and inhibits vascular endothelial growth factor (VEGF) secretion by a range of human cancer cell lines, in concentrations that should be clinically feasible. The angiostatic activity of orally administered green tea now appears likely to reflect inhibition of the kinase activity of VEGFR-2. Glycine's angiostatic activity may be attributable to a hyperpolarizing effect on endothelial cells that decreases the activity of NADPH oxidase, now known to promote tyrosine kinase signaling in endothelial cells. The ability of TM to suppress cancer cell production of a range of angiogenic factors results at least in part from a downregulation of NF-κB activation. Dual-purpose molecular targets, whose inhibition could be expected to decrease the aggressiveness and chemoresistance of cancer cells while simultaneously impeding angiogenesis, include NF-κB, cox-2, c-Src, Stat3, and hsp90; drugs that can address these targets are now in development, and salicylates are notable for the fact that they can simultaneously inhibit NF-κB and cox-2. The potential complementary of the components of MAT should be assessed in nude mouse xenograft models.

The prognostic role of phospho-Src family kinase analysis in tongue cancer

“…Thus, we have previously studied various biological aspects of salivary gland and tongue tumors (BenIzhak et al 2005(BenIzhak et al , 2006(BenIzhak et al , 2007, examining an array of tumor markers that are part of pathways related to tumorogenicity, proliferation and apoptosis though until now we have not investigated the well-known oncogene phospho-Src family kinase. Up-regulation of phospho-Src family kinase, a nonreceptor tyrosine kinase, has been documented in numerous tumors including those derived from the colon, liver, lung and breast (Warmuth et al 2003;Martin 2004;Ishizawar and Parsons 2004;Dehm and Bonham 2004;McCarty and Block 2005;Alper and Bowden 2005;Chong et al 2005;Alvarez et al 2006). The relationship between phospho-Src family kinase activation and cancer progression is signiWcant, since phospho-Src family kinase has been found to be a critical component of multiple signaling pathways that regulate proliferation, survival, metastasis and angiogenesis.…”

Deleterious effects of silymarin on the expression of genes controlling endothelial nitric oxide synthase activity in carbon tetrachloride-treated rat livers

“…We also have preliminary results showing that silymarin inhibits phosphorylation of Akt/PKB (Ser 473 ) as well as eNOS (Ser 1177 ), probably resulting in eNOS/NO inactivation (unpublished data). Recently, this effect of silymarin has been applied to cancer prevention by antiangiogenic inhibition of VEGF/eNOS activity (McCarty and Block 2005;Jiang et al 2000).…”

Preadministration of High-Dose Salicylates, Suppressors of NF-κB Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy

“…289,290 Moreover, it should be noted that various nutraceuticals recommended for use in angiostatic therapy 298,299 may influence VEGF activity. Thus, the primary green tea catechin EGCG can inhibit VEGFR-2 (KDR/flk-1) activity in high physiological concentrations (∼1 µM) 300 ; the eicosapentaenoic acid in fish oil can inhibit the expression of this receptor 301,302 ; high-dose glycine may boost the activity of a tyrosine phosphatase, which targets this receptor (M. F. McCarty, unpublished data, 2005); and silymarin, selenium, and IGF-I down-regulation have the potential to suppress the production of VEGF by tumor cells.…”