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

被引:18
作者
Lim, Junghee [1 ]
Duong, Tam [2 ]
Lee, Guewha [1 ]
Seong, Baik Lin [3 ,4 ]
El-Rifai, Wael [5 ,6 ]
Ruley, H. Earl [7 ]
Jo, Daewoong [1 ,2 ,5 ]
机构
[1] ProCell Therapeut Inc, ProCell R&D Inst, Seoul 151050, South Korea
[2] Chonnam Natl Univ, Dept Biomed Sci, Sch Med, Kwangju 501746, South Korea
[3] Yonsei Univ, Dept Biotechnol, Seoul 120749, South Korea
[4] Yonsei Univ, Translat Res Ctr Prot Funct Control, Seoul 120749, South Korea
[5] Vanderbilt Univ, Dept Surg, Sch Med, Nashville, TN 37232 USA
[6] Vanderbilt Univ, Dept Canc Biol, Sch Med, Nashville, TN 37232 USA
[7] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Sch Med, Nashville, TN 37232 USA
关键词
Endostatin; Macromolecule transduction domain; Protein therapy; Intracellular delivery; ANGIOGENESIS INHIBITOR ENDOSTATIN; NUCLEAR IMPORT INHIBITOR; ENDOTHELIAL-CELLS; FUNCTIONAL PEPTIDES; SUPPRESSION; MECHANISMS; MEMBRANE; THERAPY; BINDING; CANCER;
D O I
10.1016/j.biomaterials.2013.05.011
中图分类号
R318 [生物医学工程];
学科分类号
0831 ;
摘要
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 phospholylation), and in beta-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. (C) 2013 Elsevier Ltd. All rights reserved.
引用
收藏
页码:6261 / 6271
页数:11
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