2. Academic Validation
  3. Nitric oxide-releasing derivatives of brefeldin A as potent and highly selective anticancer agents

Nitric oxide-releasing derivatives of brefeldin A as potent and highly selective anticancer agents

  • Eur J Med Chem. 2017 Aug 18:136:131-143. doi: 10.1016/j.ejmech.2017.05.018.
Kangtao Tian 1,  Fanxing Xu 2,  Xiang Gao 1,  Tong Han 1,  Jia Li 1,  Huaqi Pan 3,  Linghe Zang 4,  Dahong Li 5,  Zhanlin Li 1,  Takahiro Uchita 6,  Ming Gao 6,  Huiming Hua 7
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
  • 2 Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
  • 3 Shenyang Institute of Applied Ecology, Chinese Academy of Sciences, 72 Wenhua Road, Shenyang 110016, PR China. Electronic address: panhq@iae.ac.cn.
  • 4 School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
  • 5 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: lidahong0203@163.com.
  • 6 School of Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien, Nishinomiya 663-8179, Japan.
  • 7 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: huimhua@163.com.
PMID: 28494251 DOI: 10.1016/j.ejmech.2017.05.018
Abstract

A series of NO-donating mono- or diester derivatives of brefeldin A were designed, synthesized and biologically evaluated. Some derivatives exhibited potent antiproliferative activity with low IC50 values. The most potent NO-donating hybrid 13b exhibited stronger cytotoxicity against human prostate Cancer PC-3 cells, human colon carcinoma HT-29 cells and human liver Cancer HepG-2 cells than BFA with IC50 values of 25 nM, 160 nM and 180 nM, respectively. More importantly, compound 13b showed good selectivity between human normal and tumor liver cells with selectivity index of 33. Additionally, 13b released higher levels of NO in HepG-2 cells than L-02 cells. Further mechanism concerning cellular Apoptosis showed that 13b induced Apoptosis and S phase cell cycle arrest in HepG-2 cells. Incubation with 13b increased the number of HepG-2 cells with collapsed mitochondrial membrane at low concentrations in dose-dependent manner. In addition, by using the Human Apoptosis Protein Array kit, several apoptosis-related proteins, including HO-1, HO-2 and Survivin, were found to be markedly downregulated by 13b in HepG-2 cells. Furthermore, in western blot assay, 13b increased the expression of Bax, Cyt c and Caspase 3, and reduced the relative levels of Bcl-2, Bcl-xL and pro-caspase 3 in HepG-2 cells.

Keywords

Antitumor; Apoptosis; Brefeldin A; Nitric oxide.

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