Mechanism of inhibition of tumor angiogenesis by β-hydroxyisovalerylshikonin

Yusuke Komi, Yasuhiro Suzuki, Mariko Shimamura, Sachiko Kajimoto, Shigeo Nakajo, Michitaka Masuda, Masabumi Shibuya, Hiroyuki Itabe, Kentaro Shimokado, Peter Oettgen, Kazuyasu Nakaya, Soichi Kojima

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)

Abstract

Shikonin and β-hydroxyisovalerylshikonin (β-HIVS) from Lithospermum erythrorhizon inhibit angiogenesis via inhibition of vascular endothelial growth factor receptors (VEGFR) in an adenosine triphosphate-non-competitive manner, although the underlying molecular mechanism has not been fully understood. In the present study, we found that β-HIVS inhibited angiogenesis within chicken chorioallantoic membrane approximately threefold more efficiently than shikonin. β-HIVS also significantly inhibited angiogenesis in two other assays, induced either by Lewis lung carcinoma cells implanted in mouse dorsal skin or by VEGF in s.c. implanted Matrigel plugs and metastasis of Lewis lung carcinoma cells to lung. Therefore, using β-HIVS as a bioprobe, we investigated the molecular mechanism of shikonin's anti-angiogenic actions. β-HIVS inhibited the phosphorylation and expression of VEGFR2 and Tie2 without affecting VEGFR1 and fibroblast growth factor receptor 1 levels. β-HIVS suppressed the phosphorylation but not the expression of extracellular signal-regulated kinase, and an Sp1-dependent transactivation of the VEGFR2 and Tie2 promoters, thereby suppressing the proliferation of vascular endothelial and progenitor cells. This was mimicked by an Sp1 inhibitor mithramycin A and partially rescued by Sp1 overexpression. These results implicate potential use of shikonin and β-HIVS as leading compounds for clinical application in the future by virtue of their unique properties including: (i) inhibition of VEGFR2 and Tie2 phosphorylation in an adenosine triphosphate-non-competitive manner; (ii) simultaneous inhibition of the phosphorylation and expression of VEGFR2 and Tie2; and (iii) bifunctional inhibition of the growth in endothelial cells and vascular remodeling.

Original languageEnglish
Pages (from-to)269-277
Number of pages9
JournalCancer science
Volume100
Issue number2
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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