Article

Monocarbonyl curcumin analog A2 potently inhibits angiogenesis by inducing ROS-dependent endothelial cell death

Authors: Bin Liu1, Liu-su Cui2, Bo Zhou3, Ling-ling Zhang1, Zhi-hui Liu1, Lu Zhang1
1 College of Bioengineering, Henan University of Technology, Zhengzhou 450001, China
2 Morphological laboratory, Xinxiang Medical University, Xinxiang 453003, China
3 State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
Correspondence to: Lu Zhang: zhanglu@haut.edu.cn,
DOI: 10.1038/s41401-019-0224-x
Received: 27 November 2018
Accepted: 26 February 2019
Advance online: 18 April 2019

Abstract

Excessive and abnormal vessel growth plays a critical role in the pathogenesis of many diseases, such as cancer. Angiogenesis is one of the hallmarks of cancer growth, invasion, and metastasis. Discovery of novel antiangiogenic agents would provide new insights into the mechanisms of angiogenesis, as well as potential drugs for cancer treatment. In the present study, we investigated the antiangiogenic activity of a series of monocarbonyl analogs of curcumin synthesized previously in our lab. We found that curcumin analog A2 displayed the full potential to be developed as a novel antiangiogenic agent. Curcumin analog A2 at and above 20 μM dramatically inhibited the migration and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro, new microvessels sprouting from the rat aortic rings ex vivo and newly formed microvessels in chicken chorioallantoic membranes (CAMs) and Matrigel plus in vivo. We further demonstrated that curcumin analog A2 exerted its antiangiogenic activity mainly through inducing endothelial cell death via elevating NADH/NADPH oxidase-derived ROS. Curcumin analog A2 at the antiangiogenic concentrations also triggered autophagy in HUVECs, but this process is neither a pre-requisite for toxicity, leading to the cell death nor a protective response against the toxicity of curcumin analog A2. In conclusion, we demonstrate for the first time the potent antiangiogenic activity of the monocarbonyl curcumin analog A2, which could serve as a promising potential therapeutic agent for the prevention and treatment angiogenesis-related diseases, such as cancer.
Keywords: monocarbonyl curcumin analog; angiogenesis; apoptosis; autophagy; necroptosis; reactive oxygen species; vascular endothelial cell; bafilomycin A1; wortmannin

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