Curcumolide, a unique sesquiterpenoid from Curcuma wenyujin displays anti-angiogenic activity and attenuates ischemia-induced retinal neovascularization

Weiwei Lin; Hongfeng Tu; Yao Zhu; Yijian Guan; Hui Liu; Wei Ling; Pengcheng Yan; Jianyong Dong

doi:10.1016/j.phymed.2019.152923

Curcumolide, a unique sesquiterpenoid from Curcuma wenyujin displays anti-angiogenic activity and attenuates ischemia-induced retinal neovascularization

Phytomedicine. 2019 Nov:64:152923. doi: 10.1016/j.phymed.2019.152923. Epub 2019 Apr 12.

Authors

Weiwei Lin¹, Hongfeng Tu¹, Yao Zhu¹, Yijian Guan¹, Hui Liu¹, Wei Ling¹, Pengcheng Yan¹, Jianyong Dong²

Affiliations

¹ Pharmacy School, Wenzhou Medical University, A509, Pharmacy School Building, Wenzhou, Zhejiang Province 325035, PR China.
² Pharmacy School, Wenzhou Medical University, A509, Pharmacy School Building, Wenzhou, Zhejiang Province 325035, PR China. Electronic address: jianyd@wmu.edu.cn.

PMID: 31450226
DOI: 10.1016/j.phymed.2019.152923

Abstract

Background: Targeting vascular endothelial growth factor is a common treatment strategy for neovascular eye disease, a leading cause of visual impairment and blindness. However, these approaches are limited or carry various complications. Therefore, there is an urgent need for the development of unique therapeutic approaches.

Purpose: To investigate the anti-angiogenic effects of curcumolide and its mechanism of action.

Methods /study designs: In this study, we examine the effects of curcumolide on the process of vasculature formation, including cell proliferation, migration, tube formation and apoptosis in vitro using human umbilical vascular endothelial cells (HUVECs). We also assess the anti-angiogenic effects of curcumolide in vivo using a mouse model of oxygen induced retinopathy (OIR). The mechanism of anti-angiogenic effects was investigated by measuring the expression level of various signaling proteins and the molecular docking simulations.

Results: Intravitreal injection of curcumolide reduced the formation of retinal neovascular tufts and VEGFR2 phosphorylation in the murine OIR model at concentrations administered without definite cellular and retinal toxicities. Curcumolide suppressed VEGF-induced HRMECs proliferation, migration and tube formation in a dose-dependent manner. Meanwhile, it promoted caspase-dependent apoptosis. Curcumolide also inhibited VEGF-induced phosphorylation of VEGFR-2 tyrosine kinase, and suppressed downstream protein kinases of VEGFR2, including Src, FAK, ERK, AKT, and mTOR in HRMECs. In silico study revealed that curcumolide bound with ATP-binding sites of the VEGFR2 kinase unit by the formation of a hydrogen bond and hydrophobic interactions.

Conclusion: Curcumolide has anti-angiogenic activity in HUVECs and in a murine OIR model of ischemia-induced retinal neovascularization, and it might be a potential drug candidate for the treatment of proliferative diabetic retinopathy.

Keywords: Curcumolide; Endothelial cell apoptosis; Retinal neovascularization; VEGFR2 signaling.

MeSH terms

Angiogenesis Inhibitors / chemistry
Angiogenesis Inhibitors / isolation & purification
Angiogenesis Inhibitors / pharmacology*
Animals
Apoptosis / drug effects
Cell Movement / drug effects
Cell Proliferation / drug effects
Curcuma / chemistry*
Human Umbilical Vein Endothelial Cells / drug effects
Humans
Intravitreal Injections
Male
Mice
Mice, Inbred C57BL
Molecular Docking Simulation
Phosphorylation
Retinal Neovascularization / drug therapy*
Sesquiterpenes / chemistry
Sesquiterpenes / isolation & purification
Sesquiterpenes / pharmacology*
Vascular Endothelial Growth Factor Receptor-2 / metabolism*

Substances

Angiogenesis Inhibitors
Sesquiterpenes
curcumolide
KDR protein, human
Vascular Endothelial Growth Factor Receptor-2