Tanshinone I inhibits tumor angiogenesis by reducing Stat3 phosphorylation at Tyr705 and hypoxia-induced HIF-1α accumulation in both endothelial and tumor cells

Oncotarget. 2015 Jun 30;6(18):16031-42. doi: 10.18632/oncotarget.3648.

Abstract

Tanshinone I (Tanshinone-1), a major active principle of Salvia miltiorrhiza (Danshen), has been shown to overcome tumor drug resistance and metastasis. Here we report that tanshinone-1 inhibits angiogenesis. Tanshinone-1 inhibited proliferation, migration and tube formation of vascular endothelial cells, rat aortic ring sprouting and the neovascularization of the chick chorioallantoic membrane in a concentration-dependent manner. In endothelial cells, tanshinone-1 almost completely inhibited phosphorylation of Stat3 at Tyr705 regardless of hypoxia or normoxia but only slightly decreased the hypoxia-induced HIF-1α accumulation. In tumor cells, contrastively, tanshinone-1 could not only make phosphorylation of Stat3 at Tyr705 disappear but also reduce the hypoxia-induced accumulation of HIF-1α to its baseline levels at normoxia. Consequently, VEGF secretion from tumor cells was reduced, which could potentiate the direct inhibition of tanshinone-1 on endothelial cells. Together with its overcoming tumor drug resistance and metastasis, our results reveal unique characteristics of tanshinone-1 and its improved derivatives as promising angiogenesis inhibitors.

Keywords: HIF-1α; Stat3; VEGF; angiogenesis; tanshinone I.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abietanes / pharmacology*
  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Aorta / metabolism
  • Aorta / pathology
  • Apoptosis
  • Blotting, Western
  • Cell Movement
  • Cell Proliferation
  • Chickens
  • Chorioallantoic Membrane / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Hypoxia / physiopathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Neoplasms / blood supply
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Neoplasms / prevention & control*
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / prevention & control*
  • Phosphorylation / drug effects
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Tumor Cells, Cultured
  • Tyrosine / metabolism*

Substances

  • Abietanes
  • Antineoplastic Agents, Phytogenic
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • tanshinone
  • Tyrosine