A Novel HDAC6 Inhibitor Enhances the Efficacy of Paclitaxel Against Ovarian Cancer Cells

Ovarian cancer cells overexpress HDAC6, and selective HDAC6 inhibitors have been considered potential new drugs for ovarian cancer either alone or in combination with other anticancer agents. We screened 46 potential novel HDAC6 inhibitors in ES-2 ovarian cancer cells and showed that compound <b>25253</b> demonstrated the most potent anti-proliferative activity and effective synergy with paclitaxel, which was also validated in TOV21G ovarian cancer cells. The combination of <b>25253</b> and paclitaxel significantly induced subG1 and apoptotic cells, revealed by PI staining assay and Annexin V-FITC/PI double staining assay, respectively. Western blot analysis showed downregulation of Bcl-2 and Bcl-XL, and upregulation of Bax and Bak, indicating that apoptosis was mediated through the intrinsic pathway. The combination increased γ-H2AX and p-p53 protein levels, suggesting the induction of DNA damage. Furthermore, HDAC6 was downregulated and acetylated α-tubulin was profoundly increased. Compound <b>25253</b> enhanced the inhibitory effect of paclitaxel on cell migration and invasion, possibly due to the extensive accumulation of acetylated α-tubulin, which affected microtubule dynamics. Taken together, the combination of <b>25253</b> and paclitaxel synergistically inhibited the growth, migration, and invasion of ovarian cancer cells and induced apoptosis, providing supporting evidence that the combination of HDAC6 inhibitors and paclitaxel may be a promising treatment strategy for ovarian cancer.