Preclinical development of a bifunctional cancer cell homing, PKCε inhibitory peptide for the treatment of head and neck cancer

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide, comprising ∼50% of all malignancies in some developing nations. Our recent work identified protein kinase Cε (PKCε) as a critical and causative player in establishing an aggressive phenotype in HNSCC. In this study, we investigated the specificity and efficacy of HN1-PKCε, a novel bifunctional cancer cell homing, PKCε inhibitory peptide, as a treatment for HNSCC. HN1-PKCε peptide was designed by merging two separate technologies and synthesized as a capped peptide with two functional modules, HN1 (cancer cell homing) and PKCε (specific PKCε inhibitory), connected by a novel linker module. HN1-PKCε 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-PKCε penetrated HNSCC cells in a dose- and time-dependent manner. Consistent with these in vitro observations, systemic injection of HN1-PKCε resulted in selective delivery of HN1-PKCε into UMSCC1 xenografts in nude mice. HN1-PKCε blocked the translocation of active PKCε in UMSCC1 cells, confirming HN1-PKCε as a PKCε inhibitor. HN1-PKCε 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-PKCε significantly (83 ± 1% inhibition; P < 0.02) retards the growth of UMSCC1 xenografts in nude mice. Our work indicates that the bifunctional HN1-PKCε inhibitory peptide represents a promising novel therapeutic strategy for HNSCC. ©2009 American Association for Cancer Research.