Abstract 4908: Antennapedia "trojan" peptide delivers p21 protein resulting in tumor eradication

The purpose of this study is to utilize the “trojan horse” approach to deliver an effector function to cancer cells in vitro and in vivo. Many cell-translocating trojan peptides have been studied in the context of therapeutic protein delivery, including the homeodomain region of the Drosophila Antennapedia protein. The mechanism of transduction of this peptide relies on the presence of basic aminoacids arranged in helical conformations, which are important for lipid interactions and for penetration of the membrane. The tumor-suppressor protein p21 is important in many key cell division processes including G1 arrest leading to apoptosis of damaged cells. Restoring p21 protein to tumor cells lacking functional p21 could lead to tumor cells regaining higher chemosensitivity and the ability to die upon genotoxic insult. Our experiments investigate the tumor inhibitory and therapeutic potential of a fusion protein comprising of the ‘trojan’ peptide Antennapedia and p21. The effects of administration of Antennapedia-p21 on the growth of cultured cancer cells and on tumors implanted into nude mice were evaluated. In vitro studies showed that nuclear localization of p21 protein could be achieved using the Antennapedia carrier. The efficacy of this treatment on cells was also determined in combination with conventional chemotherapy. Treatment with Antp-p21 induced cell-cycle arrest leading to the inhibition of tumor cell growth. Intra-venous administration of the fusion protein to tumor-bearing mice inhibited tumor growth and prolonged overall survival. Furthermore, co-administration of the fusion protein with conventional chemotherapeutic agents resulted in enhanced growth inhibitory effects, tumor eradication in 40% of animals and significant reduction in tumor burden in 100% of animals. In conclusion, our findings show that we can utilize the “trojan horse” approach to deliver an effector function to cancer cells in vitro and in vivo and achieve tumor eradication. The efficacy of our anti-tumor growth modality in combination with conventionally used anti-neoplastic medication suggests that it can be considered as a promising therapeutic drug for the management of a wide range of carcinomas.