The cucurbitacins E, D and I: Investigation of their cytotoxicity toward human chondrosarcoma SW 1353 cell line and their biotransformation in man liver

International audience; Cucurbitacins are a class of natural compounds known for their numerous ă potential pharmacological effects. The purpose of this work was to ă compare the cytotoxicity of three cucurbitacins I, D, E on the ă chondrosarcoma SW 1353 cancer cell line and to investigate their ă biotransformation in man. Cucurbitacins I and D showed a very strong ă cytotoxicity, which was higher than that of cytochalasin D, used as a ă drug reference. Almost 100% of the cells were apoptotic as observed by ă DNA fragmentation (TUNEL assay) after 12 h with cucurbitacins I and D (1 ă mu M) and cucurbitacin E (10 mu M). In terms of IC50 values, ă cucurbitacins I and E presented a higher toxicity compared to that of ă cucurbitacin D (MTT assay). Cucurbitacin E was readily hydrolyzed by ă human hepatic microsomes, leading to cucurbitacin I (K-m 22 mu M, V-max ă 571 nmol/mg proteins/min). On the other hand, the three cucurbitacins ă were hydroxylated at a very low extent, but they were sulfated and ă glucuronidated. In terms of V-max/K-m, the cucurbitacin E was the best ă substrate of UDP-glucuronosyltransferases. This study shows that ă cucurbitacins I, D and E present a potent cytotoxic activity toward the ă chondrosarcoma SW 1353 cell line and are metabolized as sulfate and ă glucuronide conjugates. (C) 2012 Elsevier Ireland Ltd. All rights ă reserved.