The effect of tetrathiomolybdate on cytokine expression, angiogenesis, and tumor growth in squamous cell carcinoma of the head and neck
ABSTRACT To assess the effect of tetrathiomolybdate on cytokine expression, angiogenesis, and tumor growth rate in human squamous cell carcinoma (SCC).
Three human SCC cell lines were used in this study for both in vitro and in vivo investigations. Conditioned media from untreated and tetrathiomolybdate-treated cell lines were compared with regard to cytokine levels, endothelial cell chemotaxis, endothelial cell tubule formation, and migration and the ability to induce angiogenesis in a rat aortic ring array. In vivo UM-SCC-38 was seeded onto tissue-engineered scaffolds and surgically implanted into the flanks of immunodeficient mice. Tumor growth rates and the level of angiogenesis were compared after 2 weeks of therapy.
A tertiary care facility.
In this study, we demonstrate that tetrathiomolybdate significantly decreases the secretion of interleukin 6 and basic fibroblast growth factor by head and neck SCC (HNSCC) cell lines in vitro. Furthermore, we demonstrate that tetrathiomolybdate significantly decreases the secretion of interleukin 6 and basic fibroblast growth factor by HNSCC cell lines in vitro. Furthermore, tetrathiomolybdate treatment of HNSCC cell lines results in significantly decreased endothelial cell chemotaxis, tubule formation, and neovascularization in a rat aortic ring assay. This in vitro evidence of decreased angiogenesis by tetrathiomolybdate is confirmed in vivo by using a severe combined immunodeficiency disorder mouse model in which tetrathiomolybdate therapy is shown to prevent human blood vessel formation. Finally, human HNSCC implanted into immunodeficient mice grow to a much larger size in untreated mice compared with those treated with 0.7 mL/kg per day of oral tetrathiomolybdate.
These findings illustrate the ability of tetrathiomolybdate to down-regulate proinflammatory and proangiogenic cytokines in HNSCC. These observations are potentially exciting from a clinical perspective because a global decrease in these cytokines may decrease tumor aggressiveness and reverse the resistance to chemotherapy and radiation therapy seen in this tumor type.
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- "The mechanism by which ATM exerts its anti-angiogenic and anti-cancer effect has been investigated in several research studies. ATM has been shown to decrease the secretion of several cytokines, that are crucial for the progression and survival of cancer cells, including VEGF-A,B, bFGF, IL- 6 TNF-a   . Additionally, NF K B signaling is one of the important pathways in maintaining the proliferation and survival of cancer cells. "
ABSTRACT: This study examines the target specificity of tetrathiomolybdate (ATM), an anti-angiogenic, anti-tumor agent against the viability / proliferation of arterial, venous, capillary endothelial and tumor cells. Cells were seeded at 10 or 100% density (to measure viability / proliferation respectively) in medium +/- 0-250 uM ATM. Viability and proliferation were measured by metabolic labeling-colorimetry. One-way ANOVA + Bonferroni testing examined base metabolism; Dunnett's testing was used for viability/proliferation. Venous proliferation showed high ATM sensitivity (50% reduction ~ > or =5 uM ATM, p<0.01), capillary proliferation was inhibited > or =10 uM (p<0.05). Arterial endothelium were less sensitive to ATM, (50% inhibition ~ > or = 20 uM, p<0.01). YPEN-1 were inhibited >50 uM ATM. Capillary viability was inhibited > or =20 microM ATM (p<0.01); venous, arterial and tumor viability show less ATM sensitivity. Our data suggest that venous and capillary endothelial proliferation are important targets in ATM therapy, but that other vascular segments and tumor cells may be less influenced.Inflammation Research 01/2008; 56(12):515-9. DOI:10.1007/s00011-007-7025-2 · 2.14 Impact Factor
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ABSTRACT: Copper stimulates the proliferation and migration of endothelial cells and is required for the secretion of several angiogenic factors by tumour cells. Copper chelation decreases the secretion of many of these factors. Serum copper levels are upregulated in many human tumours and correlate with tumour burden and prognosis. Copper chelators reduce tumour growth and microvascular density in animal models. New orally active copper chelators have enabled clinical trials to be undertaken, and there are several studies ongoing. A unifying mechanism of action by which copper chelation inhibits endothelial cell proliferation and tumour secretion of angiogenic factors remains to be elucidated, but possible targets include copper-dependent enzymes, chaperones, and transporters.Journal of Mammary Gland Biology and Neoplasia 11/2005; 10(4):299-310. DOI:10.1007/s10911-006-9003-7 · 5.00 Impact Factor
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ABSTRACT: Angiogenesis is a multi-step process which involves endothelial cell sprouting from existing blood vessels, followed by migration, proliferation, alignment and tube formation. Tetrathiomolybdate (TM) is a multi-hit antiangiogenic agent with actions against multiple angiogenic pathways. These inhibitory effects of TM are attributed to its potent copper level-reducing property. Copper is needed for activation of various angiogenic pathways at the transcriptional and protein levels. The direct effects of TM on angiogenesis of endothelial cells were examined using an in vitro sprout-forming system. It was shown that depletion of copper by TM selectively repressed bFGF-induced, but not VEGF-induced sprout formation (an early angiogenic step). This model permitted the separation of VEGF- and bFGF- induced early angiogenesis in vitro, and indicated the existence of mechanistic differences between bFGF- and VEGF- induced early angiogenic events.Anticancer research 01/2006; 26(3A):1753-8. · 1.87 Impact Factor