Document Detail


Preclinical development of a bifunctional cancer cell homing, PKCepsilon inhibitory peptide for the treatment of head and neck cancer.
MedLine Citation:
PMID:  19567682     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide, comprising approximately 50% of all malignancies in some developing nations. Our recent work identified protein kinase Cepsilon (PKCepsilon) as a critical and causative player in establishing an aggressive phenotype in HNSCC. In this study, we investigated the specificity and efficacy of HN1-PKCepsilon, a novel bifunctional cancer cell homing, PKCepsilon inhibitory peptide, as a treatment for HNSCC. HN1-PKCepsilon peptide was designed by merging two separate technologies and synthesized as a capped peptide with two functional modules, HN1 (cancer cell homing) and PKCepsilon (specific PKCepsilon inhibitory), connected by a novel linker module. HN1-PKCepsilon preferentially internalized into UMSCC1 and UMSCC36 cells, two HNSCC cell lines, in comparison with oral epithelial cells: 82.1% positive for UMSCC1 and 86.5% positive for UMSCC36 compared with 1.2% positive for oral epithelial cells. In addition, HN1-PKCepsilon penetrated HNSCC cells in a dose- and time-dependent manner. Consistent with these in vitro observations, systemic injection of HN1-PKCepsilon resulted in selective delivery of HN1-PKCepsilon into UMSCC1 xenografts in nude mice. HN1-PKCepsilon blocked the translocation of active PKCepsilon in UMSCC1 cells, confirming HN1-PKCepsilon as a PKCepsilon inhibitor. HN1-PKCepsilon inhibited cell invasion by 72 +/- 2% (P < 0.001, n = 12) and cell motility by 56 +/- 2% (P < 0.001, n = 5) in UMSCC1 cells. Moreover, in vivo bioluminescence imaging showed that HN1-PKCepsilon significantly (83 +/- 1% inhibition; P < 0.02) retards the growth of UMSCC1 xenografts in nude mice. Our work indicates that the bifunctional HN1-PKCepsilon inhibitory peptide represents a promising novel therapeutic strategy for HNSCC.
Authors:
Liwei Bao; Michael A Gorin; Manchao Zhang; Alejandra C Ventura; William C Pomerantz; Sofia D Merajver; Theodoros N Teknos; Anna K Mapp; Quintin Pan
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2009-06-30
Journal Detail:
Title:  Cancer research     Volume:  69     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-07-16     Completed Date:  2009-09-25     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5829-34     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / chemical synthesis,  pharmacology*
Apoptosis / drug effects
Cell Line, Transformed
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Drug Evaluation, Preclinical
Head and Neck Neoplasms / drug therapy*,  metabolism,  pathology
Humans
Mice
Mice, Nude
Peptides / chemical synthesis,  pharmacology*
Protein Kinase C-epsilon / antagonists & inhibitors*,  metabolism
Protein Transport / drug effects
Treatment Outcome
Tumor Burden / drug effects
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
P50CA97248/CA/NCI NIH HHS; R01 CA135096/CA/NCI NIH HHS; R01 CA135096-02/CA/NCI NIH HHS; R01CA135096/CA/NCI NIH HHS; R01CA77612/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/HN1-PKCepsilon peptide; 0/Peptides; EC 2.7.11.13/Protein Kinase C-epsilon
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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