Preclinical Development of a Bifunctional Cancer Cell Homing, PKCε Inhibitory Peptide for the Treatment of Head and Neck Cancer

Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide, comprising similar to 50% of all malignancies in some developing nations. Our recent work identified protein kinase C epsilon (PKC epsilon) as a critical and causative player in establishing an aggressive phenotype in HNSCC. In this study, we investigated the specificity and efficacy of HN1-PKC epsilon a novel bifunctional cancer cell homing, PKC epsilon inhibitory peptide, as a treatment for HNSCC. HN1-PKC epsilon peptide was designed by merging two separate technologies and synthesized as a capped peptide with two functional modules, HN1 (cancer cell homing) and PKC epsilon (specific PKC epsilon inhibitory), connected by a novel tinker module. HN1-PKC epsilon 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-PKC epsilon penetrated HNSCC cells in a dose- and time-dependent manner. Consistent with these in vitro observations, systemic injection of HN1-PKC epsilon resulted in selective delivery of HN1-PKC epsilon into UMSCC1 xenografts in nude mice. HN1-PKC epsilon blocked the translocation of active PKC epsilon in UMSCC1 cells, confirming HN1-PKC epsilon as a PKC epsilon inhibitor. HN1-PKC epsilon 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-PKC epsilon significantly (83 +/- 1% inhibition; P < 0.02) retards the growth of UMSCC1 xenografts in nude mice. Our work indicates that the bifunctional HN1-PKC epsilon inhibitory peptide represents a promising novel therapeutic strategy for HNSCC. [Cancer Res 2009;69(14):5829-34]