Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis

Fujita, Masato; Hayashi, Izumi; Yamashina, Shohei; Itoman, Moritoshi; Murakami, Masataka

doi:10.1016/s0006-291x(02)00496-5

Cited by 217 publications

(165 citation statements)

References 26 publications

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“…It was suggested that angiotensin II played crucial roles in promoting tumor angiogenesis and cardiovascular remodeling through the induction of various growth factors, 19) which may affect the localization of tight junction proteins. 20) However, studies that reveal the relationship between angiotensin II and tight junctions are limited.…”

Section: Discussionmentioning

confidence: 99%

Telmisartan Increases the Permeability of Endothelial Cells through Zonula Occludens-1

Bian

Chen

2009

Biological & Pharmaceutical Bulletin

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Angiotensin receptor-1 blockers (ARBs) have been used for the treatment of atherosclerosis. Tight junctions are very important in the regulation of cellular permeability which may have a profound role in atherosclerosis. The relationship between them is unresolved. The expression and distribution of zonula occludens-1 (ZO-1), the permeability of cultured endothelial cells, and the activity of phosphatidylinositol 3-kinase (PI3K) were all detected with various methods after cultured endothelial cells were exposed to valsartan and the special ARB telmisartan or combined with PI3K inhibitor wortmannin or the peroxisome proliferator-activated receptor gamma antagonist GW9662. We found that telmisartan but not valsartan downregulated ZO-1 mRNA and protein levels, disrupted the distribution of ZO-1 in cultured endothelial cells, and increased the permeability of endothelial cells in a dose-dependent manner. When the PI3K inhibitor wortmannin was used, the effect induced by telmisartan was at least partly reversed. The role of the PI3K signaling pathway was further confirmed in the PI3K activity assay. GW9662 significantly blocked telmisartan-induced ZO-1 changes. Our results suggest that telmisartan disrupts the continuous pericellular distribution of ZO-1, downregulates the expression of ZO-1 in endothelial cells, and increases the permeability of endothelial cells at least partly through PI3K and the peroxisome proliferator-activated receptor gamma-dependent pathway.

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Section: Discussionmentioning

confidence: 99%

Telmisartan Increases the Permeability of Endothelial Cells through Zonula Occludens-1

Bian

Chen

2009

Biological & Pharmaceutical Bulletin

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“…Microvessel density in the tumor and stroma was assessed as a parameter of tumor-associated angiogenesis according to the established methods described previously (Borre et al, 1998;Fujita et al, 2002;Weidner et al, 1991). The individual microvessels were counted in a ϫ200 field microscope.…”

Section: Determination Of Angiogenesismentioning

confidence: 99%

COX-2/VEGF-Dependent Facilitation of Tumor-Associated Angiogenesis and Tumor Growth in vivo

Yoshida

Aoki

Hayashi

et al. 2003

Laboratory Investigation

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SUMMARY:Nonsteroidal anti-inflammatory drugs are known to suppress the occurrence and progression of malignancies such as colorectal cancers. However, the precise mechanism of these actions remains unknown. We have evaluated the role of an inducible cyclo-oxygenase (COX-2) in tumor-associated angiogenesis and tumor growth, and identified the downstream molecules involved using a ddy mouse model of sponge angiogenesis, which mimics tumor angiogenesis and is COX-2 and vascular endothelial growth factor (VEGF) dependent. In this model, VEGF expression was down-regulated by selective COX-2 inhibition with NS-398. To find out the involvement of COX-2/VEGF pathway in tumor-associated angiogenesis, we estimated angiogenesis occurring around implanted Millipore chambers containing sarcoma-180 (S-180) cells or Lewis lung carcinoma cells. Daily oral administration of NS-398 or of aspirin, a nonselective COX inhibitor, suppressed angiogenesis seen around the Millipore chambers. S-180 cells implanted in ddy mice formed substantial tumors with extensive angiogenesis markedly suppressed by aspirin and COX-2 inhibitors NS-398 and JTE522, but not by mofezolac, an inhibitor of constitutive COX-1. Tumor-associated angiogenesis was also significantly suppressed by a neutralizing antibody against VEGF. S-180 tumor growth in the subcutaneous tissues was also suppressed by aspirin, COX-2 selective inhibitors, and the VEGF antibody, but not by the COX-1 inhibitor. These results demonstrate that the inhibition of the COX-2/VEGF-dependent pathway was effective in tumor-associated angiogenesis, tumor growth, and tumor metastasis. (Lab Invest 2003, 83:1385-1394.

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“…The growth of sarcoma 180 (S-180) cells and of fibrosarcoma cells was strongly inhibited by administration of TCV-116 in the diet at a dose of approximately 100 mg kg -1 day -1 , along with a marked reduction in tumourassociated angiogenesis. 49,50 Basal cell carcinoma Captopril also reduces chronic benign and malignant skin reactions in the radiation treatment field. The beneficial effect of captopril on the severity of radiation-induced epilation and moist desquamation and the incidence of skin tumours was determined for up to 52 weeks in male rats.…”

Section: Brain Tumoursmentioning

confidence: 99%

Angiotensin inhibition and malignancies: a review

Rosenthal

Gavras

2009

J Hum Hypertens

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After an early report that patients treated with angiotensin-converting enzyme (ACE) inhibitors had a lower than expected incidence of cancers, there was a large number of publications investigating the possible pathophysiological mechanism mediating this effect, as well as population studies comparing the incidence of cancers in patients treated with agents inhibiting the reninangiotensin system with their incidence in the general population. Several mechanisms are proposed to explain a potential anti-tumour activity of such agents in vitro in experimental animal models. However, the population studies are mostly inconclusive, although they do suggest a possible interaction between ACE genotypes and susceptibility to altered behaviour of certain tumours.

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Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis

Cited by 217 publications

References 26 publications

Telmisartan Increases the Permeability of Endothelial Cells through Zonula Occludens-1

Telmisartan Increases the Permeability of Endothelial Cells through Zonula Occludens-1

COX-2/VEGF-Dependent Facilitation of Tumor-Associated Angiogenesis and Tumor Growth in vivo

Angiotensin inhibition and malignancies: a review

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