Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease

• Published in: Nature communications Vol. 4; no. 1; p. 2735
• Main Authors: Ueki, Nobuhide, Lee, Siyeon, Sampson, Nicole S., Hayman, Michael J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.11.2013; Nature Publishing Group
• Subjects: 631/67/1059/602; 631/92/436/2388; 692/308/153; Animals; Antineoplastic Agents - therapeutic use; Cathepsin L - metabolism; Cell Line, Tumor; Cell Survival; Gene Expression Regulation, Enzymologic - physiology; Gene Expression Regulation, Neoplastic - physiology; Histone Deacetylases - metabolism; Humanities and Social Sciences; Humans; Mice; multidisciplinary; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - enzymology; Prodrugs; Puromycin - chemistry; Puromycin - metabolism; Puromycin - therapeutic use; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms3735

Eradication of cancer cells while minimizing damage to healthy cells is a primary goal of cancer therapy. Highly selective drugs are urgently needed. Here we demonstrate a new prodrug strategy for selective cancer therapy that utilizes increased histone deacetylase (HDAC) and tumour-associated protease activities produced in malignant cancer cells. By coupling an acetylated lysine group to puromycin, a masked cytotoxic agent is created, which is serially activated by HDAC and an endogenous protease cathepsin L (CTSL) that remove the acetyl group first and then the unacetylated lysine group liberating puromycin. The agent selectively kills human cancer cell lines with high HDAC and CTSL activities. In vivo studies confirm tumour growth inhibition in prodrug-treated mice bearing human cancer xenografts. This cancer-selective cleavage of the masking group is a promising strategy for the next generation of anticancer drug development that could be applied to many other cytotoxic agents. Selective targeting of cancer cells may improve therapeutic efficacy while reducing adverse effects. Here, Ueki et al. report selective activation of an anticancer drug upon removal of an acetylated lysine group by histone deacetylases and the tumour-associated protease cathepsin L.