Effects of nitric oxide modulation on tumour blood flow and microvascular permeability in C6 glioma

Swaroop, G; Malcolm, George P.; Kelly, Paul A.; Ritchie, Isobel M.; Ir, Whittle

doi:10.1097/00001756-199808030-00028

Cited by 23 publications

(11 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Taken together, our findings indicate that Notch inactivation-mediated inhibition of eNOS activity results in vascular dysfunction in larger vessels of the tumor vasculature affecting tumor growth. Our data support other studies showing that eNOS inhibition using genetic or pharmacologic strategies reduces tumor blood flow and growth (5)(6)(7)(8)31). …”

Section: Endothelial Cell-specific Notch Inhibition Reduces Functionasupporting

confidence: 91%

“…3 and 4). Genetic ablation of eNOS and pharmacologic approaches have shown that NO contributes to tumor progression by maintaining blood flow (5-7), inducing vascular hyperpermeability (7,8), recruiting pericytes and promoting vessel morphogenesis (4), and reducing endothelial cell-leucocyte interactions (6). eNOS is activated by phosphorylation of the Ser1117 residue, which is regulated by multiple signaling pathways (1,2).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Endothelial-Specific Notch Blockade Inhibits Vascular Function and Tumor Growth through an eNOS-Dependent Mechanism

et al. 2014

View full text Add to dashboard Cite

Notch signaling is important for tumor angiogenesis induced by vascular endothelial growth factor A. Blockade of the Notch ligand Dll4 inhibits tumor growth in a paradoxical way. Dll4 inhibition increases endothelial cell sprouting, but vessels show reduced perfusion. The reason for this lack of perfusion is not currently understood. Here we report that inhibition of Notch signaling in endothelial cell using an inducible binary transgenic system limits VEGFAdriven tumor growth and causes endothelial dysfunction. Neither excessive endothelial cell sprouting nor defects of pericyte abundance accompanied the inhibition of tumor growth and functional vasculature. However, biochemical and functional analysis revealed that endothelial nitric oxide production is decreased by Notch inhibition. Treatment with the soluble guanylate cyclase activator BAY41-2272, a vasorelaxing agent that acts downstream of endothelial nitric oxide synthase (eNOS) by directly activating its soluble guanylyl cyclase receptor, rescued blood vessel function and tumor growth. We show that reduction in nitric oxide signaling is an early alteration induced by Notch inhibition and suggest that lack of functional vessels observed with Notch inhibition is secondary to inhibition of nitric oxide signaling. Coculture and tumor growth assays reveal that Notch-mediated nitric oxide production in endothelial cell requires VEGFA signaling. Together, our data support that eNOS inhibition is responsible for the tumor growth and vascular function defects induced by endothelial Notch inhibition. This study uncovers a novel mechanism of nitric oxide production in endothelial cells in tumors, with implications for understanding the peculiar character of tumor blood vessels. Cancer Res; 74(9); 2402-11. Ó2014 AACR.

show abstract

Section: Endothelial Cell-specific Notch Inhibition Reduces Functionasupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Endothelial-Specific Notch Blockade Inhibits Vascular Function and Tumor Growth through an eNOS-Dependent Mechanism

et al. 2014

View full text Add to dashboard Cite

show abstract

“…), have been shown to induce significantly different and sometimes opposing changes in blood flow in solid tumors and corresponding normal tissues [28]. In addition, alteration of blood flow in glioma and normal brain by nitric oxide modulators, has been observed in gliomabearing rats [29]. A favorable pharmacological modulation of the blood flow rates in conjunction with magnetic targeting could therefore be adopted to obtain enhancement in both the extent and selectivity of nanoparticle accumulation in gliomas.…”

Section: Discussionmentioning

confidence: 99%

Glioma selectivity of magnetically targeted nanoparticles: A role of abnormal tumor hydrodynamics

Chertok

David

Huang

et al. 2007

Journal of Controlled Release

View full text Add to dashboard Cite

Magnetic targeting is a promising strategy for achieving localized drug delivery. Application of this strategy to treat brain tumors, however, is complicated by their deep intracranial location, since magnetic field density cannot be focused at a distance from an externally applied magnet. This study intended to examine whether, with magnetic targeting, pathological alteration in brain tumor flow dynamics could be of value in discriminating the diseased site from healthy brain. To address this question, the capture of magnetic nanoparticles was first assessed in vitro using a simple flow system under theoretically estimated glioma and normal brain flow conditions. Secondly, accumulation of nanoparticles via magnetic targeting was evaluated in vivo using 9L-glioma bearing rats. In vitro results that predicted a 7.6-fold increase in nanoparticle capture at glioma-versus contralateral brainrelevant flow rates were relatively consistent with the 9.6-fold glioma selectivity of nanoparticle accumulation over the contralateral brain observed in vivo. Based on these finding, the in vitro ratio of nanoparticle capture can be viewed as a plausible indicator of in vivo glioma selectivity. Overall, it can be concluded that the decreased blood flow rate in glioma, reflecting tumor vascular abnormalities, is an important contributor to glioma-selective nanoparticle accumulation with magnetic targeting.

show abstract

“…There is evidence that the reverse can also apply at least in rat glioma (Swaroop et al 1998) and mouse liver tumour (Jordan et al 2000) models, in which administration of NO • donor drugs significantly enhanced blood flow.…”

Section: Blood Flowmentioning

confidence: 99%

Targeting nitric oxide for cancer therapy

Hirst

Robson

2007

Journal of Pharmacy and Pharmacology

102

View full text Add to dashboard Cite

A blueprint for the ideal anticancer molecule would include most of the properties of nitric oxide (NO • ), but the ability to exploit these characteristics in a therapeutic setting requires a detailed understanding of the biology and biochemistry of the molecule. These properties include the ability of NO • to affect tumour angiogenesis, metastasis, blood flow and immuno surveillance. Furthermore NO• also has the potential to enhance both radio-and chemotherapy. However, all of these strategies are dependent on achieving appropriate levels of NO

show abstract

Effects of nitric oxide modulation on tumour blood flow and microvascular permeability in C6 glioma

Cited by 23 publications

References 7 publications

Endothelial-Specific Notch Blockade Inhibits Vascular Function and Tumor Growth through an eNOS-Dependent Mechanism

Endothelial-Specific Notch Blockade Inhibits Vascular Function and Tumor Growth through an eNOS-Dependent Mechanism

Glioma selectivity of magnetically targeted nanoparticles: A role of abnormal tumor hydrodynamics

Targeting nitric oxide for cancer therapy

Contact Info

Product

Resources

About