In vivo pharmacokinetic and anticancer studies of hh-n25, a selective inhibitor of topoisomerase i, and hormonal signaling for treating breast cancer

Bashir Lawal, Yu Cheng Kuo, Maryam Rachmawati Sumitra, Alexander T.H. Wu, Hsu Shan Huang

研究成果: 雜誌貢獻文章同行評審

6 引文 斯高帕斯(Scopus)

摘要

Purpose: Breast cancer is the most frequently diagnosed cancer globally, and the leading cause of cancer-associated mortality among women. The efficacy of most clinical che-motherapies is often limited by poor pharmacokinetics and the development of drug resistance by tumors. In a continuing effort to explore small molecules as alternative therapies, we herein evaluated the therapeutic potential of HH-N25, a novel nitrogen-substituted anthra [1,2-c][1,2,5]thiadiazole-6,11-dione derivative. Methods: We evaluated the in vivo pharmacokinetic properties and maximum tolerated dose (MTD) of HH-N25 in rats. We also characterized the compound for in vitro and in vivo anticancer activities and its inhibitory effects against DNA topoisomerases and hormonal signaling in breast cancer. Furthermore, we used molecular docking to analyse the ligand– receptor interactions between the compound and the targets. Results: The maximum serum concentration (Cmax), half-life (t1/2 beta), mean residence time (MRT), oral clearance (CL/f), and apparent volume of distribution (VD/f) of HH-N25 were 1446.67 ± 312.05 ng/mL, 4.51 ± 0.27 h, 2.56 ± 0.16 h, 8.32 ± 1.45 mL/kg/h, and 1.26 ± 0.15 mL/kg, respectively, after single-dose iv administration at 3 mg/kg body weight. HH-N25 had potent anticancer activity against a panel of human breast cancer cell lines with 50% inhibitory concentrations (IC50) ranging 0.045±0.01~4.21±0.05 µM. The drug also demonstrated marked in vivo anticancer activity at a tolerated dose and prolonged the survival duration of mice without unacceptable toxicities based on body weight changes in human tumor xenograft models. In addition, HH-N25 exhibited a dose-dependent inhibition of topoisomerase I and ligand-mediated activities of progesterone and androgen receptors. Conclusion: HH-N25 represents a new molecular entity that selective suppressed TOP1 and hormonal signaling, and shows potent antitumor activities in human breast cancer cells in vitro and in vivo. HH-N25 thus represents a promising anticancer agent that warrants further preclinical and clinical exploration.
原文英語
頁(從 - 到)4901-4913
頁數13
期刊Journal of Inflammation Research
14
DOIs
出版狀態已發佈 - 2021

ASJC Scopus subject areas

  • 免疫學和過敏
  • 免疫學

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