Involvement of COX-2 in VEGF-induced angiogenesis via P38 and JNK pathways in vascular endothelial cells

Wu, Guifu; Luo, Jincai; Rana, Jamal S.; Laham, Roger J.; Sellke, Frank W.; Li, Jian

doi:10.1016/j.cardiores.2005.09.019

Cited by 168 publications

(144 citation statements)

References 19 publications

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“…Functionally, JNK is an important part of learning and memory systems (Sherrin et al, 2011). And there is at least one study suggesting that JNK may mediate angiogenesis in human umbilical vein endothelial cells (Wu et al, 2006). Our present findings might be consistent with this broader literature.…”

Section: Discussionsupporting

confidence: 93%

Delayed Inhibition of c-Jun N-Terminal Kinase Worsens Outcomes after Focal Cerebral Ischemia

Murata¹,

Fujiwara²,

Seo³

et al. 2012

Journal of Neuroscience

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The stress-activated protein kinase c-Jun N-terminal kinase (JNK) is a central regulator in neuronal death cascades. In animal models of cerebral ischemia, acute inhibition of JNK reduces infarction and improves outcomes. Recently however, emerging data suggest that many neuronal death mediators may have biphasic properties-deleterious in the acute stage but potentially beneficial in the delayed stage. Here, we hypothesized that JNK may also have biphasic actions, so some caution may be required in the development of JNK inhibitors for stroke. Sprague Dawley rats underwent 90 min transient occlusions of the middle cerebral artery. Acute treatment (10 min poststroke) with the JNK inhibitor SP600125 reduced infarction volumes. In contrast, delayed treatment (7 d poststroke) worsened infarction volumes and neurological outcomes. Immunostaining of peri-infarct cortex showed that JNK inhibition suppressed surrogate markers of neurovascular remodeling, including matrix metalloproteinase-9 in GFAP-positive astrocytes and microvascular density. Consistent with these in vivo data, SP600125 significantly suppressed in vitro angiogenesis in rat brain endothelial cultures. Our data provide initial proof-of-concept that the neuronal death target JNK may also participate in endogenous processes of neurovascular remodeling and recovery after cerebral ischemia.

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Section: Discussionsupporting

confidence: 93%

Delayed Inhibition of c-Jun N-Terminal Kinase Worsens Outcomes after Focal Cerebral Ischemia

Murata¹,

Fujiwara²,

Seo³

et al. 2012

Journal of Neuroscience

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“…Sorafenib inhibits multiple receptors, including members of the VEGFR family. VEGF activates JNK in human umbilical vascular endothelial cells (46) in a pathway that likely involves cdc42 and VEGFR-2 (47,48). Given the pleiotropic nature of sorafenib and proteasome inhibitors, it is likely that multiple pathways are contributing to the synergistic activation of JNK that we report in response to combined treatment.…”

Section: Discussionmentioning

confidence: 75%

Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways

Yu¹,

Friday²,

Lai³

et al. 2006

Molecular Cancer Therapeutics

104

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This study was undertaken to characterize preclinical cytotoxic interactions for human malignancies between the multikinase inhibitor sorafenib (BAY 43-9006) and proteasome inhibitors bortezomib or MG132. Multiple tumor cell lines of varying histiotypes, including A549 (lung adenocarcinoma), 786-O (renal cell carcinoma), HeLa (cervical carcinoma), MDA-MB-231 (breast), K562 (chronic myelogenous leukemia), Jurkat (acute T-cell leukemia), MEC-2 (B-chronic lymphocytic leukemia), and U251 and D37 (glioma), as well as cells derived from primary human glioma tumors that are likely a more clinically relevant model were treated with sorafenib or bortezomib alone or in combination. Sorafenib and bortezomib synergistically induced a marked increase in mitochondrial injury and apoptosis, reflected by cytochrome c release, caspase-3 cleavage, and poly(ADPribose) polymerase degradation in a broad range of solid tumor and leukemia cell lines. These findings were accompanied by several biochemical changes, including decreased phosphorylation of vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-B, and Akt and increased phosphorylation of stress-related c-Jun NH 2 -terminal kinase (JNK). Inhibition of Akt was required for synergism, as a constitutively active Akt protected cells against apoptosis induced by the combination. Alternatively, the JNK inhibitor SP600125 could also protect cells from apoptosis induced by the combination, indicating that both inhibition of Akt and activation of JNK were required for the synergism. These findings show that sorafenib interacts synergistically with bortezomib to induce apoptosis in a broad spectrum of neoplastic cell lines and show an important role for the Akt and JNK pathways in mediating synergism. Further clinical development of this combination seems warranted. [Mol Cancer Ther 2006;5(9):2378 -87]

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“…For example, blocking the VEGF pathway abolishes the proangiogenic and protumorigenic effects of EETs (11,(35)(36)(37). COX-2 inhibition has been shown to inhibit VEGF production (38); thus, coinhibition of COX-2 may reduce or eliminate the proangiogenic effects of EETs. As expected here, we also found that PTUPB reduced the plasma VEGF level by 50%.…”

Section: Cox-2/seh Dual Inhibitor Ptupb Inhibits Primary Tumor Growthmentioning

confidence: 99%

Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis

Zhang

Panigrahy

Hwang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

114

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Prostaglandins derived from the cyclooxygenase (COX) pathway and epoxyeicosatrienoic acids (EETs) from the cytochrome P450/ soluble epoxide hydrolase (sEH) pathway are important eicosanoids that regulate angiogenesis and tumorigenesis. COX-2 inhibitors, which block the formation of prostaglandins, suppress tumor growth, whereas sEH inhibitors, which increase endogenous EETs, stimulate primary tumor growth and metastasis. However, the functional interactions of these two pathways in cancer are unknown. Using pharmacological inhibitors as probes, we show here that dual inhibition of COX-2 and sEH synergistically inhibits primary tumor growth and metastasis by suppressing tumor angiogenesis. COX-2/sEH dual pharmacological inhibitors also potently suppress primary tumor growth and metastasis by inhibiting tumor angiogenesis via selective inhibition of endothelial cell proliferation. These results demonstrate a critical interaction of these two lipid metabolism pathways on tumorigenesis and suggest dual inhibition of COX-2 and sEH as a potential therapeutic strategy for cancer therapy.

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Involvement of COX-2 in VEGF-induced angiogenesis via P38 and JNK pathways in vascular endothelial cells

Abstract: COX-2 plays an important role in VEGF-induced angiogenesis via p38 and JNK kinase activation pathways. These findings suggest that the cardioprotective role of COX-2 may be, at least in part, through its angiogenic activity.

Cited by 168 publications

References 19 publications

Delayed Inhibition of c-Jun N-Terminal Kinase Worsens Outcomes after Focal Cerebral Ischemia

Delayed Inhibition of c-Jun N-Terminal Kinase Worsens Outcomes after Focal Cerebral Ischemia

Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways

Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis

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