A novel peptide specifically binding to interleukin-6 receptor (gp80) inhibits angiogenesis and tumor growth.
Experimental and clinical findings support the essential role of interleukin (IL)-6 in the pathogenesis of various human cancers and provide a rationale for targeted therapeutic investigations. A novel peptide, S7, which selectively binds to IL-6 receptor (IL-6R) alpha chain (gp80) and broadly inhibits IL-6-mediated events, was identified using phage display library screening. The synthetic S7 peptide specifically bound to soluble IL-6R as well as cognate human IL-6R alpha, resulting in a dose-dependent blockade of the interaction between IL-6 and IL-6R alpha. S7 peptide prevents IL-6-mediated survival signaling and sensitizes cervical cancer cells to chemotherapeutic compounds in vitro. The in vitro analysis of antiangiogenic activity showed that S7 peptide substantially inhibits IL-6-induced vascular endothelial growth factor-A expression and angiogenesis in different cancer cell lines. Furthermore, S7 peptide was bioavailable in vivo, leading to a significant suppression of IL-6-induced vascular endothelial growth factor-mediated cervical tumor growth in severe combined immunodeficient mice. These observations show the feasibility of targeting IL-6/IL-6R interaction using the small peptide and highlight its potential in the clinical applications.
Su
Jen-Liang
JL
Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan.
Lai
Kuo-Pao
KP
Chen
Chi-An
CA
Yang
Ching-Yao
CY
Chen
Pei-Sheng
PS
Chang
Chiao-Chia
CC
Chou
Chia-Hung
CH
Hu
Chi-Lun
CL
Kuo
Min-Liang
ML
Hsieh
Chang-Yao
CY
Wei
Lin-Hung
LH
D020533:Angiogenesis Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000378:metabolism* / Q000494:pharmacology*; D019151:Peptide Library; D011485:Protein Binding; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013379:Substrate Specificity; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays; D000093242:Interleukin-6 Inhibitors
D020533:Angiogenesis Inhibitors; D015850:Interleukin-6; D009842:Oligopeptides; D019151:Peptide Library; D019947:Receptors, Interleukin-6; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors; C467484:VEGFA protein, human