Inhibiting bladder tumor growth with a cell penetrating R11 peptide derived from the p53 C-terminus

// Tingting Zhang 1, * , Kaijie Wu 1, * , Chen Ding 2, * , Kangwei Sun 1 , Zhenfeng Guan 1 , Xinyang Wang 1 , Jer-Tsong Hsieh 3 , Dalin He 1 , Jinhai Fan 1 1 Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, China 2 Department of Urology, Xiangyang Central Hospital, Hubei University of Arts and Science, Xiangyang, Hubei Province, China 3 Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA * These authors have contributed equally to this work Correspondence to: Jinhai Fan, e-mail: jinhaif029@126.com Keywords: bladder cancer, cell penetrating peptide, p53 C-terminus, targeted therapy, metastatic tumor Received: April 20, 2015      Accepted: September 28, 2015      Published: October 08, 2015 ABSTRACT Urothelial carcinoma of the bladder (UCB) is the most common malignancy of the urinary tract, nearly half of which contains a mutation in TP53 gene. Hence, therapeutic approach by restoring functional p53 protein in cancer cells will be beneficial. Recent studies have demonstrated the inhibition of cancer cell growth by p53 reactivation using a peptide derived from the p53 C-terminus (p53C). However, the outcome of reactivating p53 in controlling bladder cancer development is limited by its efficiency and specificity of peptide delivery, especially in metastatic animal models. Herein, we report that the cell penetrating peptide (polyarginine, R11)-conjugated p53C can exhibit a preferential uptake and growth inhibit of UCB cells expressing either mutant or wild-type TP53 by the activation of p53-dependent pathway. R11-p53C peptide treatment of preclinical orthotopic and metastatic bladder cancer models significantly decreased the tumor burden and increased the lifespan without a significant cytotoxicity. Based on these results, we believe that R11-p53C peptide has therapeutic potential for primary and metastatic bladder cancer, and R11-mediated transduction may be a useful strategy for the therapeutic delivery of large tumor suppressor molecules to tumor cells in vitro and in vivo .