p28-mediated Activation of p53 in G2/M Phase of the Cell Cycle Enhances the Efficacy of DNA Damaging and Antimitotic Chemotherapy

Abstract

p28 is an anionic cell-penetrating peptide of 28 amino acids that activates wild type and mutated p53, leading subsequently to selective inhibition of CDK2 and cyclin A expression and G2/M cell cycle arrest. In this study, we investigated the cytotoxic effects of p28 treatment alone and in combination with DNA damaging and anti-mitotic agents on human cancer cells. p28 enhanced the cytotoxic activity of lower concentrations (IC20-50) of DNA damaging drugs (doxorubicin, dacarbazine, temozolamide) or anti-mitotic drugs (paclitaxel, docetaxel) in a variety of cancer cells expressing wild type or mutated p53. Mechanistic investigations revealed that p28 induced a post-translational increase in the expression of wild type or mutant p53 and p21, resulting in cell cycle inhibition at G2/M phase. Thus, the enhanced activity of these anticancer agents in combination with p28 was facilitated through the p53/p21/CDK2 pathway. Taken together, these results highlight a new approach to maximize the efficacy of chemotherapeutic agents while reducing dose-related toxicity.