title: The cucurbitacins E, D and I: investigation of their cytotoxicity toward human chondrosarcoma SW 1353 cell line and their biotransformation in man liver.
abstract: Cucurbitacins are a class of natural compounds known for their numerous potential pharmacological effects. The purpose of this work was to compare the cytotoxicity of three cucurbitacins I, D, E on the chondrosarcoma SW 1353 cancer cell line and to investigate their biotransformation in man. Cucurbitacins I and D showed a very strong cytotoxicity, which was higher than that of cytochalasin D, used as a drug reference. Almost 100% of the cells were apoptotic as observed by DNA fragmentation (TUNEL assay) after 12 h with cucurbitacins I and D (1 μM) and cucurbitacin E (10 μM). In terms of IC(50) values, cucurbitacins I and E presented a higher toxicity compared to that of cucurbitacin D (MTT assay). Cucurbitacin E was readily hydrolyzed by human hepatic microsomes, leading to cucurbitacin I (K(m) 22 μM, V(max) 571 nmol/mg proteins/min). On the other hand, the three cucurbitacins were hydroxylated at a very low extent, but they were sulfated and glucuronidated. In terms of V(max)/K(m), the cucurbitacin E was the best substrate of UDP-glucuronosyltransferases. This study shows that cucurbitacins I, D and E present a potent cytotoxic activity toward the chondrosarcoma SW 1353 cell line and are metabolized as sulfate and glucuronide conjugates.
authors.affiliation: UMR 7561 CNRS-Université Lorraine, School of Medicine, 9 Avenue de la forêt de Haye, BP 184, F-54505 Vandœuvre-lès-Nancy, Cedex, France. suziabbas@yahoo.com
authors.forename: Suzanne
authors.initials: S
authors.lastname: Abbas
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Vincourt
authors.forename: Lamice
authors.initials: L
authors.lastname: Habib
authors.forename: Patrick
authors.initials: P
authors.lastname: Netter
authors.forename: Hélène
authors.initials: H
authors.lastname: Greige-Gerges
authors.forename: Jacques
authors.initials: J
authors.lastname: Magdalou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002813:Chondrosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054728:Cucurbitacins / Q000493:pharmacokinetics* / Q000494:pharmacology*; D053938:DNA Fragmentation; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D020128:Inhibitory Concentration 50; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D054728:Cucurbitacins; D014453:Glucuronosyltransferase