Systemic administration of a protein kinase (CK2) peptide inhibitor reduces solid tumor growth in mice

FARINA HG; PERERA Y; HERNANDEZ I; MENDOZA O; SERRANO JM; REYES O; GOMEZ DE; GOMEZ RE; ACEVEDO BE; ALONSO DF; PEREA SE

Los Angeles, USA

Congreso; Annual Meeting 2007 of the American Association for Cancer Research; 2007

American Association for Cancer Research

Exploitation of kinases as cancer therapeutic targets is continuously growing and its clinical validation becomes a reality as therapies with some specific inhibitors have showed clinical benefit in cancer patients. Protein kinase CK2 is a very conserved serine/threonine kinase involved in the phosphorylation of a plethora of substrates in the cell. CK2 is essential for different cell functions like gene expression, cell growth, cell survival, chromatin remodelling, and protection of cells against apoptosis. Further to the findings above mentioned the potential of CK2 as a particularly effective target for cancer treatment has been experimentally validated by different groups. Studies in transgenic models of cancer have demonstrated that CK2 overexpression displays a great oncogenic potential and tumorigenicity. Likewise, CK2 signal is uniformly dysregulated 3- to 7- fold in different cancer types and also it has been associated with aggressive tumor behaviour in human squamous cell carcinoma of head and neck cancer. The antitumor efficacy of the CK2 inhibitors so far describe has not been extensively evaluated in cancer animal models. We have previously demonstrated that a proapoptotic cyclic peptide termed P15 delivered into the cells by the Tat cell penetrating peptide, was able to abrogate the CK2 phosphorylation and induce tumor regression when injected directly into solid tumors in mice. Here, we explore the antitumor effect by systemic administration of P15-Tat during five consecutive days through either intraperitoneal or endovenous route. Importantly, great inhibition of tumor growth and significant survival were observed when P15-Tat peptide was administered at different doses (2 - 40 mg/kg) both in syngeneic murine tumors (TC-1 lung carcinoma) and human tumors xenografted in nude mice (H-125 lung carcinoma and HeLa cervical adenocarcinoma). In line with this, the systemic administration of P15-Tat induced the cytoplasmic expression of the proapoptotic protein prohibitin in the tumor site. Furthermore, we evidence that 99mTc-labeled P15-Tat peptide was certainly accumulated on the tumors after administration by both routes. This work describes the first evidences of antitumor efficacy of a CK2 phosphorylation inhibitor by systemic administration and suggest a broader spectrum for this peptide in cancer targeted therapy.