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

Nobuhide Ueki (), Siyeon Lee, Nicole S. Sampson and Michael J. Hayman
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Nobuhide Ueki: Stony Brook University
Siyeon Lee: Stony Brook University
Nicole S. Sampson: Stony Brook University
Michael J. Hayman: Stony Brook University

Nature Communications, 2013, vol. 4, issue 1, 1-8

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms3735

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