Inhibiting bladder tumor growth with a cell penetrating R11 peptide derived from the p53 C-terminus
Tingting Zhang1, Kaijie Wu1, Chen Ding2
1Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
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.
Insights
Restoring p53 function with R11-p53C peptide effectively inhibits urothelial carcinoma of the bladder (UCB) growth. This targeted therapy shows promise for treating both primary and metastatic bladder cancer with minimal toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Drug Delivery
Background:
- Urothelial carcinoma of the bladder (UCB) is a common cancer, with TP53 mutations found in nearly half of cases.
- Restoring functional p53 protein is a potential therapeutic strategy for UCB.
- Current p53 reactivation methods face challenges in delivery efficiency and specificity, particularly in metastatic models.
Purpose of the Study:
- To develop and evaluate a novel peptide-based therapy for bladder cancer by conjugating p53 C-terminus peptide (p53C) with a cell-penetrating peptide (polyarginine, R11).
- To assess the efficacy and specificity of the R11-p53C peptide in inhibiting UCB cell growth and tumor progression in preclinical models.
Main Methods:
- Conjugation of p53C with R11 to create R11-p53C peptide.
- In vitro testing for preferential uptake and growth inhibition in UCB cells (mutant and wild-type TP53).
- In vivo evaluation in preclinical orthotopic and metastatic bladder cancer models.
Main Results:
- R11-p53C peptide demonstrated preferential uptake and significant growth inhibition of UCB cells via p53-dependent pathway activation.
- Treatment with R11-p53C peptide in preclinical models led to decreased tumor burden and increased lifespan.
- Therapy showed no significant cytotoxicity in the tested models.
Conclusions:
- R11-p53C peptide exhibits therapeutic potential for both primary and metastatic bladder cancer.
- R11-mediated delivery is a viable strategy for introducing large tumor suppressor molecules into cancer cells in vitro and in vivo.
