2013
DOI: 10.1038/srep01035
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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. Modifica… Show more

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Cited by 142 publications
(168 citation statements)
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“…In the first experiment, the medium of wild-type Hek293 cells was compared with that of cells overexpressing two human cysteine amidases, acid ceramidase (AC) and N-acylethanolamine acid amidase (NAAA). These enzymes were selected because they are structurally related but exert different effects on the replication of Hek293 cells in which they are transfected; AC expression markedly enhances replication, whereas NAAA expression does not [32].…”
Section: Biological Applicationsmentioning
confidence: 99%
“…In the first experiment, the medium of wild-type Hek293 cells was compared with that of cells overexpressing two human cysteine amidases, acid ceramidase (AC) and N-acylethanolamine acid amidase (NAAA). These enzymes were selected because they are structurally related but exert different effects on the replication of Hek293 cells in which they are transfected; AC expression markedly enhances replication, whereas NAAA expression does not [32].…”
Section: Biological Applicationsmentioning
confidence: 99%
“…Karmofurun hücre yaşam oranlarına etkisi MTT yöntemiyle, apoptoz uyarım etkisi flow sitometri yöntemiyle, hücrelerdeki morfolojik deği-şiklikler ise konfokal mikroskobuyla incelendi. Karmofurun çeşitli konsantrasyonlarının (5,10,15,20,25,30,35,40,45,50, 55 ve 60 µM) 24 saat uygulanması sonucunda kontrol grubuna göre (% 100) hücrelerdeki yaşam oranları sırasıyla % 100, 77, 65, 64, 46, 38, 34, 30, 26, 20, 14 ve 9 olarak tespit edildi. Karmofurun 24 µM (IC50) dozunun 24 saat uygulanması sonucunda bu hücre populasyonundaki apoptotik hücrelerin yüzdesinin kontrol grubuna göre arttığı belirlendi.…”
Section: öZunclassified
“…Sfingolipidlerden oluşan ve hücre-lerde ikinci haberci olarak görev yapan seramid, seramid-1 fosfat (C1P), sfingozin ve sfingozin-1 fosfatın (S1P) hücre çoğalması, apoptoz, inflamasyon ve hücre döngüsü üzerine etkileri ortaya konmuştur (5,6). Bu sfingolipidlerin içe-risinde yer alan seramid hücrelerin yaşamlarını ya da ölümlerini belirleyen aracılardan birisidir (15). Tümör nekroz faktör, oksidatif stres, bü-yüme faktörlerinin baskılanması, antikanser ilaçlar, radyasyon ve UV ışını gibi stres faktörleri hücrelerde özellikle sfingomiyelinaz enzimini aktive eder, seramid yapımını uyarır ve hücrele-rin ölümüne neden olur.…”
Section: şEki̇lunclassified
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