Development of peptide inhibitor as a therapeutic agent against head and neck squamous cell carcinoma (HNSCC) targeting p38α MAP kinase

Background: The p38 alpha MAP kinase pathway is involved in inflammation, cell differentiation, growth, apoptosis and production of pro-inflammatory cytokines TNF-alpha and IL-1 beta. The overproduction of these cytokines plays an important role in cancer. The aim of this work was to design a peptide inhibitor on the basis of structural information of the active site of p38 alpha. Methods: A tetrapeptide, VWCS as p38 alpha inhibitor was designed on the basis of structural information of the ATP binding site by molecular modeling. The inhibition study of peptide with p38 alpha was performed by ELISA, binding study by Surface Plasmon Resonance and anti-proliferative assays by MIT and flow cytometry. Results: The percentage inhibition of designed VWCS against pure p38 alpha protein and serum of HNSCC patients was 70.30 and 71.5%, respectively. The biochemical assay demonstrated the K-D and IC50 of the selective peptide as 7.22 x 10(-9) M and 20.08 nM, respectively. The VWCS as inhibitor significantly reduced viability of oral cancer KB cell line with an IC50 value of 10 mu M and induced apoptosis by activating Caspase 3 and 7. Conclusions: VWCS efficiently interacted at the ATP binding pocket of p38 alpha with high potency and can be used as a potent inhibitor in case of HNSCC. General significance: VWCS can act as an anticancer agent as it potentially inhibits the cell growth and induces apoptosis in oral cancer cell-line in a dose as well as time dependent manner. Hence, p38 alpha MAP kinase inhibitor can be a potential therapeutic agent for human oral cancer. (C) 2012 Elsevier B.V. All rights reserved.