p12CDK2-AP1 Gene Therapy Strategy Inhibits Tumor Growth in an In vivo Mouse Model of Head and Neck Cancer

Abstract

Purpose: To test the potential of p12 CDK2-AP1 (p12), a cell cycle regulator and cyclin-dependent kinase-2-associating protein commonly down-regulated in head and neck squamous cell carcinoma (f70%), as a gene therapy in inhibiting head and neck squamous cell carcinoma growth in vivo. Experimental Design: We addressed the effect of p12 expression on tumor growth by using a well-established squamous cell carcinoma VII/SF floor of mouth xenograft mouse model. The effect of therapy on tumor growth was determined for: (a) no treatment, (b) PBS, (c) vehicle (1,2-dioleoyloxy-3-trimethylammonium propane:cholesterol liposomes / 5 % dextrose), (d) empty vector controls, and (e) p12-encoding vector experimental groups. Results: p12 gene therapy significantly induced antitumor effects as compared with controls, including (a) size and weight of p12-treated tumors decreased by 51% to 72% compared with all controls (P < 0.02), (b) tumor growth rate post-therapy was inhibited by 55 % to 64% compared with empty vector controls (P < 0.0001), and (c) p12 expression was higher in p12-treated than controls (P < 0.002) by two-tailed t test analyses. Mechanistically, p12 treatment affected cell turnover kinetics as assessed by apoptotic and cell proliferation indices. p12 therapy significantly increased terminal nucleotidyl transferase^mediated nick end labeling (P < 0.05) and morphology-based apoptotic indices (P < 0.05) as well as significantly decreased Ki-67 cell proliferation indices (P < 0.001) compared with controls, resulting in a net cell turnover reduction in p12-treated tumors. Conclusions: We show that this novel therapeutic modality can significantly induce antitumor responses in vivo. These results support a role for p12 as a novel tumor growth suppressor gene therapy and suggest that optimization and/or combination with current therapies may hold considerable promise in preparation for clinical trials.

Molecular mechanisms of head and neck cancer

“…Thus, CDK2AP1 is a common link between two pathways, the pRB pathway and the TGF-β pathway, both of which are affected in the process of OSCC tumorigenesis. Figueiredo et al explored this advantage to use recombinant DNA to re-express CDK2AP1 in OSCC tumors in murine models and showed successful tumor regression [105].…”

“…Gene therapy strategies are being tested and in combination with chemotherapy and radiation therapy will prove more powerful. Gene therapy approached are already being tested using adenovirus mediated p53 re-expression, liposome mediated CDK2AP1 re-expression, and antisense inhibition of EGFR [63,105,122]. Inhibitors of specific molecular targets upregulated in the tumorigenic process (EGFR, VEGF, COX-2) are also being tested, either alone or in combination with existing therapies.…”

Efficient Inhibition of Ovarian Cancer Growth and Prolonged Survival by Transfection with a Novel Pro-Apoptotic Gene, hPNAS-4, in a Mouse Model

“…For control sections, terminal deoxynucleotidyl transferase enzyme was omitted and no positive staining was observed. Positively stained cells were counted in 5–10 high-power fields (×200) and the number of positive cells for ≥500 cells counted was termed the TUNEL apoptotic index [19]. …”

Interaction between p12CDK2AP1 and a novel unnamed protein product inhibits cell proliferation by regulating the cell cycle

“…It has also been identified that p12 CDK2AP1 is involved in anti-angiogenesis modulation and the suppression of malignant biological interactions between prostate cancer and bone cells (15). The possibility of using p12 CDK2AP1 as a therapeutic target has been suggested (16). Proteins undertake numerous physiological functions, such as the regulation of enzymatic activities, the assembly of cellular components and signal transduction.…”