Feedback

Identification of a novel pyridine derivative with inhibitory activity against ovarian cancer progression in vivo and in vitro

Affiliation
Department of Gynecology ,The First Affiliated Hospital of Zhengzhou University ,Zhengzhou University ,Zhengzhou ,China
Si, Lulu;
Affiliation
Department of Gynecology ,The First Affiliated Hospital of Zhengzhou University ,Zhengzhou University ,Zhengzhou ,China
Lai, Tianjiao;
Affiliation
State Key Laboratory of Esophageal Cancer Prevention and Treatment ,Key Laboratory of Advanced Pharmaceutical Technology ,Ministry of Education of China ,School of Pharmaceutical Sciences ,Zhengzhou University ,Zhengzhou ,China
Zhao, Junru;
Affiliation
Department of Gynecology ,The First Affiliated Hospital of Zhengzhou University ,Zhengzhou University ,Zhengzhou ,China
Jin, Yuxi;
Affiliation
Department of Gynecology ,The First Affiliated Hospital of Zhengzhou University ,Zhengzhou University ,Zhengzhou ,China
Qi, Meng;
Affiliation
Department of Gynecology ,The First Affiliated Hospital of Zhengzhou University ,Zhengzhou University ,Zhengzhou ,China
Li, Mingyue;
Affiliation
Department of Gynecology ,The First Affiliated Hospital of Zhengzhou University ,Zhengzhou University ,Zhengzhou ,China
Fu, Hanlin;
Affiliation
Laboratory Animal Center ,Academy of Medical Science ,Zhengzhou University ,Zhengzhou ,China
Shi, Xiaojing;
Affiliation
State Key Laboratory of Esophageal Cancer Prevention and Treatment ,Key Laboratory of Advanced Pharmaceutical Technology ,Ministry of Education of China ,School of Pharmaceutical Sciences ,Zhengzhou University ,Zhengzhou ,China
Ma, Liying;
Affiliation
Department of Gynecology ,The First Affiliated Hospital of Zhengzhou University ,Zhengzhou University ,Zhengzhou ,China
Guo, Ruixia

Ovarian cancer is the second leading cause of death of female gynecological malignant tumor patients worldwide. Although surgery and chemotherapy have achieved dramatic achievement, the mortality remains high, resulting in the demand for new specific drug discovery. Disrupting ovarian cancer growth via histone deacetylase (HDAC) inhibition is a strategy for cancer therapy or prevention. In this work, we synthesized a novel pyridine derivative named compound H42 and investigated its anti-cancer activity in vivo and in vitro . We found that compound H42 inhibited ovarian cancer cell proliferation with IC 50 values of 0.87 μM (SKOV3) and 5.4 μM (A2780). Further studies confirmed that compound H42 induced apoptosis, intracellular ROS production, and DNA damage. Moreover, compound H42 downregulated the expression of histone deacetylase 6 (HDAC6) with a distinct increase in the acetylation of α-tubulin and heat shock protein 90 (HSP90), followed by the degradation of cyclin D1, resulting in cell cycle arrest at the G0/G1 phase. Importantly, ectopic expression of HDAC6 induced deacetylation of HSP90 and α-tubulin, while HDAC6 knockdown upregulated the acetylation of HSP90 and α-tubulin. However, in the nude xenograft mouse study, compound H42 treatment can inhibit ovarian cancer growth without obvious toxicity. These findings indicated that compound H42 inhibited ovarian cancer cell proliferation through inducing cell cycle arrest at the G0/G1 phase via regulating HDAC6-mediated acetylation, suggesting compound H42 could serve as a lead compound for further development of ovarian cancer therapeutic agents.

Cite

Citation style:
Could not load citation form.

Access Statistic

Total:
Downloads:
Abtractviews:
Last 12 Month:
Downloads:
Abtractviews:

Rights

License Holder: Copyright © 2022 Si, Lai, Zhao, Jin, Qi, Li, Fu, Shi, Ma and Guo.

Use and reproduction: