Resveratrol Regulates Pathologic Angiogenesis by a Eukaryotic Elongation Factor-2 Kinase-Regulated Pathway

Khan, Adam Z.; Dace, Dru S.; Ryazanov, Alexey G.; Kelly, Jennifer; Apte, Rajendra S.

doi:10.2353/ajpath.2010.090836

Cited by 46 publications

(43 citation statements)

References 42 publications

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“…However, IPA showed that p-38 is related to the Rac1 pathway (Figure 5B). P-38 MAPK (mitogen-activated protein kinase) plays a role in invasion, migration (21, 22) and angiogenesis (23, 24). Based on these data, we focused and started to validate by western blot the proteins involved in the Rac1/p38 pathway shown in blue color in figure 5B.…”

Section: Resultsmentioning

confidence: 99%

Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer

González-Villasana

Fuentes‐Mattei

Ivan

et al. 2015

Clinical Cancer Research

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Purpose Zoledronic acid (ZA) is being increasingly recognized for its anti-tumor properties, but the underlying functions are not well understood. In this study, we hypothesized that ZA inhibits ovarian cancer (OC) angiogenesis preventing Rac1 activation. Experimental Design The biological effects of ZA were examined using a series of in vitro (cell invasion, cytokine production, Rac1 activation, reverse-phase protein array and in vivo (orthotopic mouse models) experiments. Results There was significant inhibition of OC (HeyA8-MDR and OVCAR-5) cell invasion as well as reduced production of pro-angiogenic cytokines in response to ZA treatment. Furthermore, ZA inactivated Rac1 and decreased the levels of Pak1/p-38/matrix metalloproteinase-2 in OC cells. In vivo, ZA reduced tumor growth, angiogenesis and cell proliferation and inactivated Rac1 in both HeyA8-MDR and OVCAR-5 models. These in vivo antitumor effects were enhanced in both models when ZA was combined with nab-paclitaxel. Conclusion ZA has robust anti-tumor and anti-angiogenic activity and merits further clinical development as OC treatment.

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Section: Resultsmentioning

confidence: 99%

Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer

González-Villasana

Fuentes‐Mattei

Ivan

et al. 2015

Clinical Cancer Research

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“…A previous study reported an inhibitory effect of RSV on CNV development, specifically related to the proliferation of vascular endothelial cells [52]. RSV-induced activation of AMPK results in the phosphorylation of a serine residue of eukaryotic elongation factor 2 (eEF2) kinase, which inactivates eEF2 through threonine phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol prevents the development of choroidal neovascularization by modulating AMP-activated protein kinase in macrophages and other cell types

Nagai

Kubota

Tsubota

et al. 2014

The Journal of Nutritional Biochemistry

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The development of choroidal neovascularization (CNV) is a critical step in the pathogenesis of age-related macular degeneration (AMD), a vision-threatening disease. In this study, we used a mouse model of AMD to study the protective effects of resveratrol (RSV) supplementation against CNV as well as the underlying molecular mechanisms. Mice were orally pretreated with RSV daily for 5 days. On the fifth day, the mice underwent laser photocoagulation to induce CNV. One week after laser treatment, CNV volume was significantly lower in the RSV-treated mice compared with vehicle-treated animals. In addition, RSV treatment significantly inhibited macrophage infiltration into the retinal pigment epithelium (RPE)-choroid and suppressed the expression of inflammatory and angiogenic molecules, including vascular endothelial growth factor, monocyte chemotactic protein-1 and intercellular adhesion molecule-1. Importantly, RSV prevented the CNV-induced decrease in activated AMP-activated protein kinase and increase in activated nuclear factor-κB in the RPE-choroid complex. The regulatory effects of RSV on these molecules were confirmed in RPE, microvascular endothelial and macrophage cell lines. Inhibition of macrophage infiltration by RSV was confirmed by in vitro scratch and migration assays. RSV suppressed CNV development, reducing the levels of multiple cytokines secreted from several cell types and inhibiting macrophage migration. The direct effects of RSV on each cell type were confirmed in vitro. Although further studies are needed, RSV could potentially be applied in the clinic to prevent CNV development in AMD.

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“…For example, a study on angiogenesis in rat gliomas investigated by color Doppler ultrasound showed that resveratrol-mediated suppression of glioma growth was significantly correlated with the inhibition of macroscopic and microscopic angiogenesis (Chen et al, 2006). A very recent study demonstrated that resveratrol inhibits the proliferation and migration of vascular endothelial cells by activating eukaryotic elongation factor-2 kinase, which in turn phosphorylates and inactivates elongation factor-2, a key mediator of ribosomal transfer and protein translation (Khan et al, 2010). Functional inhibition of the kinase by gene deletion in vivo or RNA as well as pharmacological inhibition completely reverses the effects of resveratrol on blood vessel growth.…”

Section: Angiogenesismentioning

confidence: 97%