Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer Cells

• Published in: International journal of molecular sciences 2022-10, Vol.23 (21), p.13019
• Main Authors: Ovejero-Sánchez, María, Asensio-Juárez, Gloria, González, Myriam, Puebla, Pilar, Vicente-Manzanares, Miguel, Pélaez, Rafael, González-Sarmiento, Rogelio, Herrero, Ana Belén
• Format: Article
• Language: English
• Subjects: Acetylation; Antineoplastic Agents - pharmacology; Apoptosis; Cancer therapies; Cell cycle; Cell division; Cell growth; Cell Line, Tumor; Cell Proliferation; Chemoresistance; Chemotherapy; Colchicine; Cytotoxicity; Drugs; Female; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Humans; Hydrogen bonds; Hydroxamic Acids - pharmacology; Indoles - pharmacology; Laboratories; Medical prognosis; microtubule-destabilizing agents; Microtubules; Ovarian cancer; Ovarian Neoplasms - drug therapy; panobinostat; Panobinostat - pharmacology; Sulfonamides; Sulfonamides - pharmacology; Tubulin; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232113019

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 ( ) was synthetized and characterized. This compound also inhibited OC cell proliferation and induced G2/M cell cycle arrest and apoptosis. Interestingly, 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.