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&...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/13/2793 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849320919246307328 |
|---|---|
| author | An-Jui Chi Jui-Ling Hsu Yun-Xin Xiao Ji-Wang Chern Jih-Hwa Guh Chao-Wu Yu Lih-Ching Hsu |
| author_facet | An-Jui Chi Jui-Ling Hsu Yun-Xin Xiao Ji-Wang Chern Jih-Hwa Guh Chao-Wu Yu Lih-Ching Hsu |
| author_sort | An-Jui Chi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-19ac7f194e714300be834da2e38fafda |
| institution | Kabale University |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-19ac7f194e714300be834da2e38fafda2025-08-20T03:49:55ZengMDPI AGMolecules1420-30492025-06-013013279310.3390/molecules30132793A Novel HDAC6 Inhibitor Enhances the Efficacy of Paclitaxel Against Ovarian Cancer CellsAn-Jui Chi0Jui-Ling Hsu1Yun-Xin Xiao2Ji-Wang Chern3Jih-Hwa Guh4Chao-Wu Yu5Lih-Ching Hsu6School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, TaiwanSchool of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, TaiwanSchool of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, TaiwanSchool of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, TaiwanSchool of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, TaiwanSchool of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, TaiwanSchool of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, TaiwanOvarian 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.https://www.mdpi.com/1420-3049/30/13/2793HDAC6 inhibitorpaclitaxel (Taxol)ovarian cancercombination therapyapoptosis |
| spellingShingle | An-Jui Chi Jui-Ling Hsu Yun-Xin Xiao Ji-Wang Chern Jih-Hwa Guh Chao-Wu Yu Lih-Ching Hsu A Novel HDAC6 Inhibitor Enhances the Efficacy of Paclitaxel Against Ovarian Cancer Cells Molecules HDAC6 inhibitor paclitaxel (Taxol) ovarian cancer combination therapy apoptosis |
| title | A Novel HDAC6 Inhibitor Enhances the Efficacy of Paclitaxel Against Ovarian Cancer Cells |
| title_full | A Novel HDAC6 Inhibitor Enhances the Efficacy of Paclitaxel Against Ovarian Cancer Cells |
| title_fullStr | A Novel HDAC6 Inhibitor Enhances the Efficacy of Paclitaxel Against Ovarian Cancer Cells |
| title_full_unstemmed | A Novel HDAC6 Inhibitor Enhances the Efficacy of Paclitaxel Against Ovarian Cancer Cells |
| title_short | A Novel HDAC6 Inhibitor Enhances the Efficacy of Paclitaxel Against Ovarian Cancer Cells |
| title_sort | novel hdac6 inhibitor enhances the efficacy of paclitaxel against ovarian cancer cells |
| topic | HDAC6 inhibitor paclitaxel (Taxol) ovarian cancer combination therapy apoptosis |
| url | https://www.mdpi.com/1420-3049/30/13/2793 |
| work_keys_str_mv | AT anjuichi anovelhdac6inhibitorenhancestheefficacyofpaclitaxelagainstovariancancercells AT juilinghsu anovelhdac6inhibitorenhancestheefficacyofpaclitaxelagainstovariancancercells AT yunxinxiao anovelhdac6inhibitorenhancestheefficacyofpaclitaxelagainstovariancancercells AT jiwangchern anovelhdac6inhibitorenhancestheefficacyofpaclitaxelagainstovariancancercells AT jihhwaguh anovelhdac6inhibitorenhancestheefficacyofpaclitaxelagainstovariancancercells AT chaowuyu anovelhdac6inhibitorenhancestheefficacyofpaclitaxelagainstovariancancercells AT lihchinghsu anovelhdac6inhibitorenhancestheefficacyofpaclitaxelagainstovariancancercells AT anjuichi novelhdac6inhibitorenhancestheefficacyofpaclitaxelagainstovariancancercells AT juilinghsu novelhdac6inhibitorenhancestheefficacyofpaclitaxelagainstovariancancercells AT yunxinxiao novelhdac6inhibitorenhancestheefficacyofpaclitaxelagainstovariancancercells AT jiwangchern novelhdac6inhibitorenhancestheefficacyofpaclitaxelagainstovariancancercells AT jihhwaguh novelhdac6inhibitorenhancestheefficacyofpaclitaxelagainstovariancancercells AT chaowuyu novelhdac6inhibitorenhancestheefficacyofpaclitaxelagainstovariancancercells AT lihchinghsu novelhdac6inhibitorenhancestheefficacyofpaclitaxelagainstovariancancercells |