title: Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity.
abstract: The expression of acid ceramidase (AC) - a cysteine amidase that hydrolyses the proapoptotic lipid ceramide - is abnormally high in several human tumors, which is suggestive of a role in chemoresistance. Available AC inhibitors lack, however, the potency and drug-likeness necessary to test this idea. Here we show that the antineoplastic drug carmofur, which is used in the clinic to treat colorectal cancers, is a potent AC inhibitor and that this property is essential to its anti-proliferative effects. Modifications in the chemical scaffold of carmofur yield new AC inhibitors that act synergistically with standard antitumoral drugs to prevent cancer cell proliferation. These findings identify AC as an unexpected target for carmofur, and suggest that this molecule can be used as starting point for the design of novel chemosensitizing agents.
authors.affiliation: Department of Anatomy and Neurobiology, University of California , Irvine, California 92697-4625, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Realini
authors.forename: Carlos
authors.initials: C
authors.lastname: Solorzano
authors.forename: Chiara
authors.initials: C
authors.lastname: Pagliuca
authors.forename: Daniela
authors.initials: D
authors.lastname: Pizzirani
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.forename: Rosaria
authors.initials: R
authors.lastname: Luciani
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Costi
authors.forename: Tiziano
authors.initials: T
authors.lastname: Bandiera
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D055573:Acid Ceramidase / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D018432:Drug Resistance, Multiple; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D055573:Acid Ceramidase; C017367:carmofur; D005472:Fluorouracil