Antitumor effects of a novel proapoptotic peptide targeting the protein kinase CK2 in human papillomavirus-infected cells.

HERNÁN G FARINA; SILVIO E PEREA; OSVALDO REYES; HUGO SIGMAN; LUIS HERRERA; BORIS ACEVEDO

Boston

Congreso; Protein Kinase Targets; 2008

World Trade Center

Protein Kinase CK2 is a serine-threonine kinase frequently deregulated in many human tumors. Overexpression of CK2 displays a great oncogenic potential and tumorigenicity, and confers resistance to apoptosis. In addition, CK2 activates the E7 oncoprotein in cells infected with human papillomavirus (HPV). Here, we hypothesized that a peptide binder to the CK2 phosphoaceptor site could exhibit anticancer properties in vitro, in tumor animal models and in cancer patients. By screening a random cyclic peptide phage display library, we identified the CIGB-300 (also known as P15-Tat), a cyclic peptide which abrogates the CK2 phosphorylation activity in vitro. Interestingly, synthetic CIGB-300 led to a dose-dependent cytostatic and proapoptotic effect in different cell lines transformed by HPV (HeLa, SiHa and TC-1). Importantly, CIGB-300 elicited significant antitumor effect by intralesional administration in murine syngenic tumors and human tumors xenografted in nude mice. Systemic administration also reduced tumor volume. Furthermore, we evidenced tumor accumulation using 99mTc- and biotin-labeled CIGB-300 peptides after systemic and local administration. We have also evaluated the subcellular localization and penetrability of CIGB-300 peptide by fluorescence microscopy. Results showed that the peptide rapidly diffuse through the plasma membrane and accumulated into the nuclear compartment, with a prominent signal in the nucleolus. Finally, we performed a First-in-Man trial with CIGB-300 in patients with cervical malignancies. The compound was found to be safe and well tolerated in the dose range studied. These results describe the antitumor effects of a CK2 phosphorylation inhibitor and suggest a broader spectrum for this peptide in cancer targeted therapy.