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  • br Acknowledgements br Authors wish

    2019-10-21


    Acknowledgements
    Authors wish to thank Daniele Quintavalle for his help in chromatin immunoprecipitation experiments, the Vall d’Hebron Research Institute, and the University of Barcelona for support.
    Appendix A. Supplementary data
    Funding
    References
    [26] F. Desarnaud, P. Geck, C. Parkin, G. Carpinito, A.N. Makarovskiy, Gene expression profiling of the androgen independent prostate cancer Cyclosporin H demonstrates complex mechanisms mediating resistance to docetaxel, Cancer Biol. Ther. 11 (2011)
    Contents lists available at ScienceDirect
    European Journal of Pharmacology
    journal homepage: www.elsevier.com/locate/ejphar
    Molecular and cellular pharmacology
    A novel ent-kaurane diterpenoid analog, DN3, selectively kills human gastric T cancer cells via acting directly on mitochondria
    Yong-Cheng Maa,b,1, Ying-Li Zhua,1, Nan Suc, Yu Ked, Xia-Xia Fana, Xiao-Jing Shid, Hong-Min Liud, , Ai-Feng Wanga,b, a Clinical Pharmacology Laboratory, Zhengzhou University People's Hospital, No. 7, Wei Wu Road, Zhengzhou, Henan, China b Pharmacy Department, Fuwai Centeral China Cardiovascular Hospital, No.1, Fuwai Road, Zhengzhou 451464, Henan, China c College of Food and Biological Engineering, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan, China d School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China
    Keywords:
    Ent-kaurene diterpenoid derivative
    Anti-tumor
    Mitochondrion
    VDAC1
    CypD 
    Targeting mitochondria using proper pharmacological agents is considered an attractive strategy for cancer control and management. Herein, we report a newly synthetic triazole analog of Jaridonin, DN3, which exhibits more potent antitumor activity via acting directly on mitochondria. DN3 potently reduced viabilities of gastric cancer cell lines HGC-27 and MGC-803 through inducing apoptosis and cell cycle arrest. But, normal human gastric epithelial cell line GES-1 is more resistant to the growth inhibition by DN3 compared with gastric cancer cells. DN3 induced mitochondrial membrane potential (MMP) decrease and cytochrome c release in intact gastric cancer cell lines. Meanwhile, the DN3 treatment also caused the release of cytochrome c from mi-tochondria isolated from cancer cell lines in a mitochondrial permeability transition pore complex (PTPC) mediated manner, but not from mitochondria isolated from normal gastric epithelial cell. The induction of mitochondrial PTPC proteins voltage-dependent anion channel (VDAC) and cyclophilin D (CypD) were also observed in DN3-treated cells. More interestingly, DN3 mediated MMP decrease, release of cytochrome c, the expression of VDAC and CypD and apoptosis were blocked by the pretreatment of VDAC1 inhibitor (4, 4′-diisothiocyanatostilbene-2,2′-disulfonic acid, DIDS) and CypD inhibitor (cyclosporine A, CsA). In a mouse xe-nograft model of human gastric cancer, the treatment of 5 mg/kg DN3 led to significant tumor regression without affecting body weight. In conclusion, our findings indicate that DN3 is a potential agent for the treat-ment of gastric cancer through acting directly on mitochondria, and would be useful for us to design more and better anti-cancer compounds.
    1. Introduction
    Mitochondrial dysfunction was known as hallmark of cancer, which was observed as early as in the 1930s by Otto Warburg (Vyas et al., 2016). Mitochondria comparatively differ in cancer cells from normal cells, there have been numerous studies attempting to clearly trace the characteristics of mitochondria in cancer: weakened mitochondrial re-spiration, enhanced glycolysis and increased ROS generation, as well as elevated membrane potential and the alterations of mitochondrial permeability transition pore (MPTP) complex (Giampazolias and Tait, 2016; Dong and Neuzil, 2014), which provide excellent targets for anti-cancer therapy.