2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Academic Article uri icon

Overview

abstract

  • Inhibition of angiogenesis is an important new modality for cancer treatment. 2-methoxyestradiol (2ME2) is a novel antitumor and antiangiogenic agent, currently in clinical trials, whose molecular mechanism of action remains unclear. Herein, we report that 2ME2 inhibits tumor growth and angiogenesis at concentrations that efficiently disrupt tumor microtubules (MTs) in vivo. Mechanistically, we found that 2ME2 downregulates hypoxia-inducible factor-1 (HIF) at the posttranscriptional level and inhibits HIF-1-induced transcriptional activation of VEGF expression. Inhibition of HIF-1 occurs downstream of the 2ME2/tubulin interaction, as disruption of interphase MTs is required for HIF-alpha downregulation. These data establish 2ME2 as a small molecule inhibitor of HIF-1 and provide a mechanistic link between the disruption of the MT cytoskeleton and inhibition of angiogenesis.

publication date

  • April 1, 2003

Research

keywords

  • DNA-Binding Proteins
  • Estradiol
  • Microtubules
  • Neovascularization, Pathologic
  • Nuclear Proteins
  • Transcription Factors

Identity

Scopus Document Identifier

  • 10744231706

Digital Object Identifier (DOI)

  • 10.1016/s1535-6108(03)00077-1

PubMed ID

  • 12726862

Additional Document Info

volume

  • 3

issue

  • 4