2. Academic Validation
  3. 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.
PMID: 37247812 DOI: 10.1016/j.ejphar.2023.175805
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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