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

Paper ID Volume ID Publish Year Pages File Format Full-Text
6409 489 2013 11 PDF Available
Title
The effect of intracellular protein delivery on the anti-tumor activity of recombinant human endostatin
Abstract

Endostatin (ES), a 20 kDa 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.

Keywords
Endostatin; Macromolecule transduction domain; Protein therapy; Intracellular delivery
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The effect of intracellular protein delivery on the anti-tumor activity of recombinant human endostatin
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Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 34, Issue 26, August 2013, Pages 6261–6271
Authors
, , , , , , ,
Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us