Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer Cells
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 Microtub...
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MDPI AG
2022-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/21/13019 |
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| author | María Ovejero-Sánchez Gloria Asensio-Juárez Myriam González Pilar Puebla Miguel Vicente-Manzanares Rafael Pélaez Rogelio González-Sarmiento Ana Belén Herrero |
| author_facet | María Ovejero-Sánchez Gloria Asensio-Juárez Myriam González Pilar Puebla Miguel Vicente-Manzanares Rafael Pélaez Rogelio González-Sarmiento Ana Belén Herrero |
| author_sort | María Ovejero-Sánchez |
| collection | DOAJ |
| description | 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 (<b>PILA9</b>) was synthetized and characterized. This compound also inhibited OC cell proliferation and induced G2/M cell cycle arrest and apoptosis. Interestingly, <b>PILA9</b> 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. |
| first_indexed | 2024-03-09T19:01:32Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T19:01:32Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-55732a6cec514a759f75abc40cf35fce2023-11-24T05:01:03ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123211301910.3390/ijms232113019Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer CellsMaría Ovejero-Sánchez0Gloria Asensio-Juárez1Myriam González2Pilar Puebla3Miguel Vicente-Manzanares4Rafael Pélaez5Rogelio González-Sarmiento6Ana Belén Herrero7Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, SpainInstitute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, SpainInstitute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, SpainInstitute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, SpainInstitute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, SpainInstitute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, SpainInstitute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, SpainInstitute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, SpainOvarian 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 (<b>PILA9</b>) was synthetized and characterized. This compound also inhibited OC cell proliferation and induced G2/M cell cycle arrest and apoptosis. Interestingly, <b>PILA9</b> 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.https://www.mdpi.com/1422-0067/23/21/13019panobinostatmicrotubule-destabilizing agentstubulinacetylation |
| spellingShingle | María Ovejero-Sánchez Gloria Asensio-Juárez Myriam González Pilar Puebla Miguel Vicente-Manzanares Rafael Pélaez Rogelio González-Sarmiento Ana Belén Herrero Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer Cells International Journal of Molecular Sciences panobinostat microtubule-destabilizing agents tubulin acetylation |
| title | Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer Cells |
| title_full | Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer Cells |
| title_fullStr | Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer Cells |
| title_full_unstemmed | Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer Cells |
| title_short | Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer Cells |
| title_sort | panobinostat synergistically enhances the cytotoxicity of microtubule destabilizing drugs in ovarian cancer cells |
| topic | panobinostat microtubule-destabilizing agents tubulin acetylation |
| url | https://www.mdpi.com/1422-0067/23/21/13019 |
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