1. Academic Validation
  2. 221S-1a inhibits endothelial proliferation in pathological angiogenesis through ERK/c-Myc signaling

221S-1a inhibits endothelial proliferation in pathological angiogenesis through ERK/c-Myc signaling

  • Eur J Pharmacol. 2023 May 27;175805. doi: 10.1016/j.ejphar.2023.175805.
Xinye Yao 1 Yanbo Xue 2 Qiang Ma 3 Yajun Bai 4 Pu Jia 4 Yiman Zhang 5 Baochang Lai 6 Shuting He 7 Qiong Ma 2 Junbo Zhang 3 Hongyan Tian 3 Qian Yin 8 Xiaohui Zheng 9 Xiaopu Zheng 10
Affiliations

Affiliations

  • 1 Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.
  • 2 Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 3 Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Department of Peripheral Vascular, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 4 Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, China.
  • 5 Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Department of Peripheral Vascular, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.
  • 6 Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China.
  • 7 Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.
  • 8 Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Department of Peripheral Vascular, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China. Electronic address: yinqian610@xjtu.edu.cn.
  • 9 Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, China. Electronic address: zhengxh@nwu.edu.cn.
  • 10 Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. Electronic address: zhengxp001@163.com.
Abstract

Pathological angiogenesis plays a major role in many disease processes, including Cancer and diabetic retinopathy. Antiangiogenic therapy is a potential management for pathologic angiogenesis. The novel synthetic compound 221S-1a, derived from captopril, tanshinol and borneol, may have antiangiogenic properties. On the basis of MS, NMR and HPLC analysis, the structure of 221S-1a was identified. The cellular uptake and metabolism of this compound was also observed. Next, the antiangiogenic properties of 221S-1a were evaluated in tumor-xenograft and OIR models in vivo. The inhibitory properties of 221S-1a on endothelial cell proliferation, migration, tube formation and sprouting were detected in vitro. Furthermore, 221S-1a induced G1/S phase arrest was detected by PI staining flow cytometry analysis and Cyclin D, Cyclin E expression. 221S-1a inhibited ERK1/2 activation and nuclear translocation, in addition to downregulation of c-Myc, a transcription factor that regulates cell cycle progression. Molecular docking indicated the interaction of 221S-1a with the ATP-binding site of ERK2, leading to the inhibition of ERK2 phosphorylation and a concomitant inhibition of ERK1 phosphorylation. In conclusion, 221S-1a inhibited the G1/S phase transition by blocking the ERK1/2/c-Myc pathway to reduce tumor and OIR retinal angiogenesis. These novel findings suggest that 221S-1a is a potential pharmacologic candidate for treating pathological angiogenesis.

Keywords

221S-1a; Cell cycle arrest; ERK1/2; Pathological angiogenesis; c-Myc.

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