In vitro and in vivo tumor growth inhibition by a p16-mimicking peptide in p16INK4A-defective, pRb-positive human melanoma cells

✍ Scribed by Douglas M. Noonan; Anna Severino; Monica Morini; Alessandra Tritarelli; Lucrezia Manente; Igea D'Agnano; Giuseppe Starace; Alfonso Baldi; Daniela Lombardi; Adriana Albini; Armando Felsani; Marco G. Paggi

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 255 KB
• Volume: 202
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.20182

✦ Synopsis

Abstract

The cell cycle regulatory pathway responsible for the control of the late‐G1 checkpoint is found recurrently altered in human malignant melanoma, often due to lack of functional p16 or pRb (pRb‐1) proteins. Here we examined the ability of p16‐derived peptides to mimic p16 function in two exemplary human melanoma cell lines: the p16‐defective, pRb‐positive A375M cells and p16‐positive, pRb‐defective A2058 cells. The synthetic p16‐mimicking peptides strongly induced apoptosis in p16−, pRb+ A375M cells in vitro, while they had significantly less activity on p16+, pRb− A2058 cells. The most active p16‐mimicking peptide, p16‐AP9, also potently inhibited in vivo growth of the A375M melanoma. Treated tumors showed a threefold smaller volume (P < 0.025) and a significant reduction of the mitotic index and of PCNA expression. Growth of A2058 cells in vivo was not affected by treatment with the p16‐mimicking peptide. Our results demonstrate that p16‐mimicking peptides can induce apoptosis in vitro and that can inhibit tumor growth in vivo in p16‐defective, pRb‐expressing human melanoma cells, suggesting that p16‐mimicking peptides can represent a promising tool for targeted therapy in selected cancer phenotypes. © 2004 Wiley‐Liss, Inc.