title: Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease.
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.
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794-5222, USA.
authors.forename: Nobuhide
authors.initials: N
authors.lastname: Ueki
authors.forename: Siyeon
authors.initials: S
authors.lastname: Lee
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Sampson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hayman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D056668:Cathepsin L / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology; D011355:Prodrugs; D011691:Puromycin / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D011691:Puromycin; D056668:Cathepsin L; D006655:Histone Deacetylases