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

• Published in: Biochimica et biophysica acta. General subjects Vol. 1830; no. 3; pp. 2763 - 2769
• Main Authors: Gill, Kamaldeep, Singh, Abhay K., Kapoor, Vaishali, Nigam, Lokesh, Kumar, Rahul, Holla, Prasida, Das, Satya N., Yadav, Savita, Subbarao, Naidu, Mohanti, Bidhu K., Dey, Sharmistha
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.03.2013
• Subjects: active sites; adenosine triphosphate; Anticancer; antineoplastic agents; Apoptosis; binding sites; blood proteins; caspase-3; cell differentiation; cell growth; enzyme-linked immunosorbent assay; flow cytometry; head; HNSCC; humans; inflammation; inhibitory concentration 50; interleukin-1beta; mitogen-activated protein kinase; molecular models; mouth neoplasms; p38α; patients; squamous cell carcinoma; surface plasmon resonance; Tetrapeptide; tumor necrosis factor-alpha; viability; RU; RPC; HRP; MHC; DLS; TFA; NPP; p38α; SPR; Tetrapeptide; MKKK; HBTU; DMF; SP; PBS; HTVS; MAPK; MKK; ATF; HNSCC; LB; IPTG; XP; PI; Anticancer; Apoptosis
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2012.12.001

The p38α MAP kinase pathway is involved in inflammation, cell differentiation, growth, apoptosis and production of pro-inflammatory cytokines TNF-α and IL-1β. 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 p38α. A tetrapeptide, VWCS as p38α inhibitor was designed on the basis of structural information of the ATP binding site by molecular modeling. The inhibition study of peptide with p38α was performed by ELISA, binding study by Surface Plasmon Resonance and anti-proliferative assays by MTT and flow cytometry. The percentage inhibition of designed VWCS against pure p38α protein and serum of HNSCC patients was 70.30 and 71.5%, respectively. The biochemical assay demonstrated the KD and IC50 of the selective peptide as 7.22×10−9M and 20.08nM, respectively. The VWCS as inhibitor significantly reduced viability of oral cancer KB cell line with an IC50 value of 10μM and induced apoptosis by activating Caspase 3 and 7. VWCS efficiently interacted at the ATP binding pocket of p38α with high potency and can be used as a potent inhibitor in case of HNSCC. 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, p38α MAP kinase inhibitor can be a potential therapeutic agent for human oral cancer. ► p38α, an inflammatory MAP kinase plays an important role in Head and Neck Squamous Cell Carcinoma (HNSCC). ► A tetrapeptide, VWCS was designed and synthesized against the ATP binding site of the p38 α kinase. ► The peptide VWCS showed an efficient interaction with the ATP binding site as determined by the KD and IC50 value. ► VWCS also exhibited anti-cancerous activity and induced apoptosis.