A 27-amino-acid synthetic peptide corresponding to the NH2-terminal zinc-binding domain of endostatin is responsible for its antitumor activity

Cancer Res. 2005 May 1;65(9):3656-63. doi: 10.1158/0008-5472.CAN-04-1833.

Abstract

The first recombinant endostatin that elicited strong antitumor activity was expressed in Escherichia coli and administered as a suspension. Under these conditions, the protein retained its full antiangiogenic activity. Lack of requirement for a folded structure prompted us to investigate antitumor properties of synthetic peptides corresponding to different regions of endostatin. Here, we show that the entire antitumor, antimigration, and antipermeability activities of endostatin are mimicked by a 27-amino-acid peptide corresponding to the NH2-terminal domain of endostatin. This peptide contains three histidines that are responsible for zinc binding. Mutations of the zinc-binding histidines abolished its antitumor and antimigration activities, but not antipermeability properties.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Amino Acid Sequence
  • Animals
  • Carcinoma, Lewis Lung / drug therapy
  • Cell Movement / drug effects
  • Endostatins / chemistry
  • Endostatins / pharmacology*
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Histidine / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • Molecular Sequence Data
  • Pancreatic Neoplasms / drug therapy
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Protein Conformation
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays
  • Zinc / chemistry
  • Zinc / metabolism*

Substances

  • Endostatins
  • Peptide Fragments
  • Histidine
  • Zinc