1. Academic Validation
  2. Natural and synthetic flavonoids, novel blockers of the volume-regulated anion channels, inhibit endothelial cell proliferation

Natural and synthetic flavonoids, novel blockers of the volume-regulated anion channels, inhibit endothelial cell proliferation

  • Pflugers Arch. 2018 Oct;470(10):1473-1483. doi: 10.1007/s00424-018-2170-8.
Yucong Xue 1 Honglin Li 2 Yuanyuan Zhang 3 Xue Han 1 Gaohua Zhang 1 Wenya Li 4 Huiran Zhang 2 Yue Lin 1 Pingping Chen 1 Xiaorun Sun 1 Yalei Liu 1 Li Chu 1 3 Jianping Zhang 5 Mingyun Zhang 6 Xuan Zhang 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, Hebei University of Chinese Medicine, No. 326 South Xinshi Road, Shijiazhuang, 050091, Hebei, China.
  • 2 Department of Respiratory, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
  • 3 Department of Medicinal Chemistry, Hebei University of Chinese Medicine, Shijiazhuang, China.
  • 4 Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang, China.
  • 5 Department of Pharmacology, Hebei University of Chinese Medicine, No. 326 South Xinshi Road, Shijiazhuang, 050091, Hebei, China. zhangjianping14@126.com.
  • 6 Department of Radiotherapy, Cangzhou Central Hospital, No. 16 West Xinhua Road, Cangzhou, China. zhangmingyun2011@126.com.
  • 7 Department of Pharmacology, Hebei University of Chinese Medicine, No. 326 South Xinshi Road, Shijiazhuang, 050091, Hebei, China. xuan_zhangt@hotmail.com.
Abstract

Natural Flavonoids are ubiquitous in dietary Plants and vegetables and have been proposed to have Antiviral, antioxidant, cardiovascular protective, and Anticancer effects. Volume-regulated anion channels (VRACs), which are essential for cell volume regulation, have been proposed to play a key role in cell proliferation and migration, Apoptosis, transepithelial transport, and Cancer development. In this study, we screened a group of 53 structurally related natural Flavonoids and three synthetic Flavonoids for their inhibitory activities on VRAC currents. A whole-cell patch technique was used to record VRAC currents in the human embryonic kidney (HEK) 293 and human umbilical vein endothelial (HUVEC) cells. The 5'-bromo-2-deoxyuridine (BrdU) assay technique was used to investigate cell proliferation. At 100 μM, 34 of 53 compounds significantly inhibited hypotonic extrasolution-induced VRAC currents by > 50% in HEK293 cells. Among these compounds, luteolin, baicalein, eupatorin, galangin, quercetin, fisetin, karanjin, Dh-morin, genistein, irisolidone, and prunetin exhibited the highest efficacy for VRAC blockade (the mean inhibition > 80%) with IC50s of 5-13 μM and Emaxs of about 87-99%. We also studied the effects of three synthetic Flavonoids on VRAC currents in HEK293 cells. Flavoxate showed high inhibition efficacy toward VRAC currents (IC50 = 2.3 ± 0.3 μM; Emax = 91.8% ± 2.7%). Finally, these Flavonoids inhibited endogenous VRAC currents and cell proliferation in endothelial cells. This study demonstrates that natural and synthetic Flavonoids are potent VRAC current inhibitors, and VRAC inhibition by Flavonoids might be responsible for their anti-angiogenic effects.

Keywords

Fisetin; Flavonoids; Flavoxate; Galangin; Luteolin; Quercetin; VRAC.

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