The effect of intracellular protein delivery on the anti-tumor activity of recombinant human endostatin

Junghee Lim, Tam Duong, Guewha Lee, Baik Lin Seong, Wael El-Rifai, H. Earl Ruley, Daewoong Jo

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14 Citations (Scopus)

Abstract

Endostatin (ES), a 20kDa protein derived from the carboxy-terminus of collagen XVIII is a potent angiogenesis inhibitor, but clinical development has been hindered by poor clinical efficacy and insufficient functional information from which to design agents with improved activity. The present study investigated protein uptake by cells as a determinant of ES activity. We developed a cell-permeable ES protein (HM73ES) with enhanced capacity to enter cells by adding a macromolecule transduction domain (MTD). HM73ES inhibited angiogenesis-associated phenotypes in cultured endothelial cells [as assessed by tube formation, wound-healing, cell proliferation and survival assays]. These effects were accompanied by reductions in MAPK signaling (ERK phosphorylation), and in β-Catenin, c-Myc, STAT3, and VEGF protein expression. The cell-permeable ES displayed greater tissue penetration in mice and suppressed the growth of human tumor xenografts to a significantly greater extent than ES protein without the MTD sequence. Our results suggest that anti-angiogenic activities of native ES are limited at the level of protein uptake and/or subcellular localization, and that much of the activity of ES against tumors depends on one or more intracellular functions. This study will inform future efforts to understand ES function(s) and suggest strategies for improving ES-based cancer therapeutics.

Original languageEnglish
Pages (from-to)6261-6271
Number of pages11
JournalBiomaterials
Volume34
Issue number26
DOIs
Publication statusPublished - 2013 Aug 1

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All Science Journal Classification (ASJC) codes

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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