Effects of ammonium tetrathiomolybdate, an oncolytic/angiolytic drug on the viability and proliferation of endothelial and tumor cells

Carpenter, April C.; Rassam, A. J.; Jennings, Merilyn H.; Robinson-Jackson, Sherry A.; Alexander, John; Erkuran-Yilmaz, Cigdem

doi:10.1007/s00011-007-7025-2

Cited by 10 publications

(6 citation statements)

References 28 publications

(31 reference statements)

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“…Several studies emphasize that TM reduces the angiogenic activity induced by tumours [52-58], which is why TM has been proposed in the therapy of cancers. However, the effect of TM has not previously been tested when cancer cells are incubated with Mφ, which represents a more physiological context: cancer associated with inflammation.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of angiogenesis resulting from cooperation between macrophages and MDA-MB-231 breast cancer cells: proposed molecular mechanism and effect of tetrathiomolybdate

et al. 2010

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BackgroundInfiltration by macrophages (Mφ) indicates a poor prognosis in breast cancers, in particular by inducing angiogenesis. Our study aimed 1) to investigate the mechanism by which cooperation between Mφ and aggressive breast cancer cells (MDA-MB-231) induces angiogenesis; 2) to examine the effect of tetrathiomolybdate (TM) on this angiogenic activity.MethodsMφ coincubated with MDA-MB-231 were used as a model to mimic the inflammatory microenvironment. Angiogenesis induced by the culture media was tested in the chick chorioallantoic membrane (CAM). Mφ phenotype was evaluated by 1) expression of the M1 marker CD80, and secretion of interleukin 10 (IL-10), an M2 marker; 2) capacity to secrete Tumour Necrosis Factor α (TNFα) when stimulated by lipopolysaccharide/interferon γ (LPS/IFNγ); 3) ability to induce MDA-MB-231 apoptosis. To explore the molecular mechanisms involved, cytokine profiles of conditioned media from MDA-MB-231, Mφ and the coculture were characterised by an antibody cytokine array. All experiments were carried out both in presence and in absence of TM.ResultsIncubation of Mφ with MDA-MB-231 induced a pro-angiogenic effect in the CAM. It emerged that the angiogenic activity of the coculture is due to the capacity of Mφ to switch from M1 Mφ towards M2, probably due to an increase in Macrophage Colony Stimulating Factor. This M1-M2 switch was shown by a decreased expression of CD80 upon LPS/IFNγ stimulation, an increased secretion of IL-10, a decreased secretion of TNFα in response to LPS/IFNγ and an inability to potentiate apoptosis. At the molecular level, the angiogenic activity of the coculture medium can be explained by the secretion of CXC chemokines/ELR+ and CC chemokines. Although TM did not modify either the M2 phenotype in the coculture or the profile of the secreted chemokines, it did decrease the angiogenic activity of the coculture medium, suggesting that TM inhibited angiogenic activity by interfering with the endothelial cell signalling induced by these chemokines.ConclusionsCooperation between Mφ and MDA-MB-231 transformed M1 Mφ to an angiogenic, M2 phenotype, attested by secretion of CXC chemokines/ELR+ and CC chemokines. TM inhibited this coculture-induced increase in angiogenic activity, without affecting either Mφ phenotype or cytokine secretion profiles.

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Section: Discussionmentioning

confidence: 99%

Stimulation of angiogenesis resulting from cooperation between macrophages and MDA-MB-231 breast cancer cells: proposed molecular mechanism and effect of tetrathiomolybdate

et al. 2010

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“…10% confluent cultures were treated with test agents in medium assaying at time points up to 72 h. LEC growth in response to cytokines was assessed by MTT assay. 28 Cells without cytokines were used as 100% 'control' level of cell proliferation with N ¼ 8 replicates.…”

Section: 27mentioning

confidence: 99%

Differential Cytokine Responses in Human and Mouse Lymphatic Endothelial Cells to Cytokinesin Vitro

Chaitanya

Franks

Cromer

et al. 2010

Lymphatic Research and Biology

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Background: Inflammatory cytokines dysregulate microvascular function, yet how cytokines affect lymphatic endothelial cells (LEC) are unclear. Methods and Results: We examined effects of TNF-a, IL-1b, and IFN-g on LEC proliferation, endothelial cell adhesion molecule (ECAM) expression, capillary formation, and barrier changes in murine (SV-LEC) and human LECs (HMEC-1a). Results: All cytokines induced ICAM-1, VCAM-1, MAdCAM-1, and E-selectin in SV-LECs; TNF-a, IL-1b and IFN-g induced ECAMs (but not MAdCAM-1) in HMEC-1a. IL-1b increased, while IFN-g and TNF-a reduced SV-LEC proliferation. While TNF-a induced, IFN-g decreased, and IL-1b did not show any effect on HMEC-1a proliferation. TNF-a, IL-1b, and IFN-g each reduced capillary formation in SV-LEC and in HMEC-1a. TNF-a and IL-1b reduced barrier in SV-LEC and HMEC-1a; IFN-g did not affect SV-LEC barrier, but enhanced HMEC-1a barrier. Inflammatory cytokines alter LEC growth, activation and barrier function in vitro and may disturb lymphatic clearance increasing tissue edema in vivo. Conclusion: Therapies that maintain or restore lymphatic function (including cytokines blockade), may represent important strategies for limiting inflammation.

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“…Accumulating evidence indicates that TTM treatment inhibits expression and lowers circulating levels of a number of angiogenic, growth-promoting, and inflammatory mediators, such as vascular endothelial growth factor, TNFα, interleukin(IL)-1α, IL-1β, and IL-6 [12, 15]. It has also been shown that TTM at a physiologically relevant dose inhibits vascular endothelial cell proliferation [16]. Moreover, recent studies suggest that TTM inhibits expression of inflammatory mediators through attenuation of NF-κB activation [12, 17].…”

Section: Introductionmentioning

confidence: 99%

Copper chelation by tetrathiomolybdate inhibits vascular inflammation and atherosclerotic lesion development in apolipoprotein E-deficient mice

Wu¹,

Zhang²,

McMillen³

et al. 2012

Atherosclerosis

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Endothelial activation, which is characterized by upregulation of cellular adhesion molecules and pro-inflammatory chemokines and cytokines, and consequent monocyte recruitment to the arterial intima are etiologic factors in atherosclerosis. Redox-active transition metal ions, such as copper and iron, may play an important role in endothelial activation by stimulating redox-sensitive cell signaling pathways. We have shown previously that copper chelation by tetrathiomolybdate (TTM) inhibits LPS-induced acute inflammatory responses in vivo. Here, we investigated whether TTM can inhibit atherosclerotic lesion development in apolipoprotein E-deficient (apoE−/−) mice. We found that 10-week treatment of apoE−/− mice with TTM (33–66 ppm in the diet) reduced serum levels of the copper-containing protein, ceruloplasmin, by 47%, and serum iron by 26%. Tissue levels of “bioavailable” copper, assessed by the copper-to-molybdenum ratio, decreased by 80% in aorta and heart, whereas iron levels of these tissues were not affected by TTM treatment. Furthermore, TTM significantly attenuated atherosclerotic lesion development in whole aorta by 25% and descending aorta by 45% compared to non-TTM treated apoE−/− mice. This anti-atherogenic effect of TTM was accompanied by several anti-inflammatory effects, i.e., significantly decreased serum levels of soluble vascular cell and intercellular adhesion molecules (VCAM-1 and ICAM-1); reduced aortic gene expression of VCAM-1, ICAM-1, monocyte chemotactic protein-1, and pro-inflammatory cytokines; and significantly less aortic accumulation of M1 type macrophages. In contrast, serum levels of oxidized LDL were not reduced by TTM. These data indicate that TTM inhibits atherosclerosis in apoE−/− mice by reducing bioavailable copper and vascular inflammation, not by altering iron homeostasis or reducing oxidative stress.

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Effects of ammonium tetrathiomolybdate, an oncolytic/angiolytic drug on the viability and proliferation of endothelial and tumor cells

Abstract: 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.

Cited by 10 publications

References 28 publications

Stimulation of angiogenesis resulting from cooperation between macrophages and MDA-MB-231 breast cancer cells: proposed molecular mechanism and effect of tetrathiomolybdate

Stimulation of angiogenesis resulting from cooperation between macrophages and MDA-MB-231 breast cancer cells: proposed molecular mechanism and effect of tetrathiomolybdate

Differential Cytokine Responses in Human and Mouse Lymphatic Endothelial Cells to Cytokinesin Vitro

Copper chelation by tetrathiomolybdate inhibits vascular inflammation and atherosclerotic lesion development in apolipoprotein E-deficient mice

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