Panobinostat synergistically enhances the cytotoxicity of microtubule destabilizing drugs in ovarian cancer cells
[EN]Ovarian cancer (OC) is one of the most common gynecologic neoplasia and has the highest mortality rate, which is mainly due to late-stage diagnosis and chemotherapy resistance. There is an urgent need to explore new and better therapeutic strategies. We have previously described a family of Micr...
| Autores: | , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universidad de Salamanca (USAL) |
| Repositorio: | GREDOS. Repositorio Institucional de la Universidad de Salamanca |
| OAI Identifier: | oai:gredos.usal.es:10366/164472 |
| Acceso en línea: | http://hdl.handle.net/10366/164472 |
| Access Level: | acceso abierto |
| Palabra clave: | Antineiplastic agents Ovarian neoplasm Cell lines Panobinostat Microtubules Sulfonamides Indoles Apoptosis Histone Deacetylase Inhibitors Ovarian Neoplasms Hydroxamic Acids Humans Cell Line Antineoplastic Agents Cell Proliferation microtúbulos sulfonamidas neoplasias ováricas indoles humanos apoptosis antineoplásicos línea celular inhibidores de histona desacetilasas proliferación celular ácidos hidroxámicos |
| Sumario: | [EN]Ovarian cancer (OC) is one of the most common gynecologic neoplasia and has the highest mortality rate, which is mainly due to late-stage diagnosis and chemotherapy resistance. There is an urgent need to explore new and better therapeutic strategies. We have previously described a family of Microtubule Destabilizing Sulfonamides (MDS) that does not trigger multidrug-mediated resistance in OC cell lines. MDS bind to the colchicine site of tubulin, disrupting the microtubule network and causing antiproliferative and cytotoxic effects. In this work, a novel microtubule-destabilizing agent (PILA9) was synthetized and characterized. This compound also inhibited OC cell proliferation and induced G2/M cell cycle arrest and apoptosis. Interestingly, PILA9 was significantly more cytotoxic than MDS. Here, we also analyzed the effect of these microtubule-destabilizing agents (MDA) in combination with Panobinostat, a pan-histone deacetylase inhibitor. We found that Panobinostat synergistically enhanced MDA-cytotoxicity. Mechanistically, we observed that Panobinostat and MDA induced α-tubulin acetylation and that the combination of both agents enhanced this effect, which could be related to the observed synergy. Altogether, our results suggest that MDA/Panobinostat combinations could represent new therapeutic strategies against OC. |
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