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

¹ Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Medical School; ² Department of Chemistry, University of Michigan, Ann Arbor, Michigan; ³ Miller School of Medicine, University of Miami, Miami, Florida; and ⁴ Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center; ⁵ Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Medical Center, Columbus, Ohio

Requests for reprints: Quintin Pan, Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Medical Center, Cramblett Medical Clinic-Suite 4A, 456 West Tenth Avenue, Columbus, OH 43210. Phone: 614-247-4438; Fax: 614-688-4761; E-mail: Quintin.Pan{at}osumc.edu.

Key Words: Experimental Therapeutics • Head and Neck Cancer • Protein Kinase • Oncogene.

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 C (PKC) 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, a novel bifunctional cancer cell homing, PKC inhibitory peptide, as a treatment for HNSCC. HN1-PKC peptide was designed by merging two separate technologies and synthesized as a capped peptide with two functional modules, HN1 (cancer cell homing) and PKC (specific PKC inhibitory), connected by a novel linker module. HN1-PKC 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 penetrated HNSCC cells in a dose- and time-dependent manner. Consistent with these in vitro observations, systemic injection of HN1-PKC resulted in selective delivery of HN1-PKC into UMSCC1 xenografts in nude mice. HN1-PKC blocked the translocation of active PKC in UMSCC1 cells, confirming HN1-PKC as a PKC inhibitor. HN1-PKC 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 significantly (83 ± 1% inhibition; P < 0.02) retards the growth of UMSCC1 xenografts in nude mice. Our work indicates that the bifunctional HN1-PKC inhibitory peptide represents a promising novel therapeutic strategy for HNSCC. [Cancer Res 2009;69(14):5829–34]