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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.

SUBMITTER: Realini N

PROVIDER: S-EPMC3539145 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity.

Realini Natalia N Solorzano Carlos C Pagliuca Chiara C Pizzirani Daniela D Armirotti Andrea A Luciani Rosaria R Costi Maria Paola MP Bandiera Tiziano T Piomelli Daniele D

Scientific reports 20130108

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 ef ...[more]

PMID: 23301156

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