(-)-UB006: A new fatty acid synthase inhibitor and cytotoxic agent without anorexic side effects
| Autor: | Fausto G. Hegardt, Joan Francesc Mir, Kamil Makowski, Jordi Garcia, Paula Mera, Laura Herrero, Xavier Ariza, Dolors Serra, Guillermina Asins |
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| Přispěvatelé: | Universitat de Barcelona |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Side effect Cell Survival Càncer d'ovari Àcids grassos Antineoplastic Agents Apoptosis Enantiòmers Pharmacology Rats Sprague-Dawley 03 medical and health sciences Eating Mice 0302 clinical medicine Ovarian cancer Drug Discovery Cytotoxic T cell Animals Humans Fatty acids Enzyme Inhibitors Cytotoxicity Furans Cells Cultured biology Chemistry Organic Chemistry Body Weight Enzyme inhibitors General Medicine Rats Mice Inbred C57BL Fatty acid synthase 030104 developmental biology Inhibidors enzimàtics Enantiomers Biochemistry Cell culture 030220 oncology & carcinogenesis biology.protein Racemic mixture Enantiomer Fatty Acid Synthases |
| Zdroj: | Recercat. Dipósit de la Recerca de Catalunya instname Dipòsit Digital de la UB Universidad de Barcelona |
| ISSN: | 1768-3254 |
| Popis: | C75 is a synthetic anticancer drug that inhibits fatty acid synthase (FAS) and shows a potent anorexigenic side effect. In order to find new cytotoxic compounds that do not impact food intake, we synthesized a new family of C75 derivatives. The most promising anticancer compound among them was UB006 ((4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one). The effects of this compound on cytotoxicity, food intake and body weight were studied in UB006 racemic mixture and in both its enantiomers separately. The results showed that both enantiomers inhibit FAS activity and have potent cytotoxic effects in several tumour cell lines, such as the ovarian cell cancer line OVCAR-3. The (−)-UB006 enantiomer's cytotoxic effect on OVCAR-3 was 40-fold higher than that of racemic C75, and 2- and 38-fold higher than that of the racemic mixture and its opposite enantiomer, respectively. This cytotoxic effect on the OVCAR-3 cell line involves mechanisms that reduce mitochondrial respiratory capacity and ATP production, DDIT4/REDD1 upregulation, mTOR activity inhibition, and caspase-3 activation, resulting in apoptosis. In addition, central and peripheral administration of (+)-UB006 or (−)-UB006 into rats and mice did not affect food intake or body weight. Altogether, our data support the discovery of a new potential anticancer compound (−)-UB006 that has no anorexigenic side effects. |
| Databáze: | OpenAIRE |
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