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  • br Based on the difference between mitochondria from cancer

    2019-10-21


    Based on the difference between mitochondria from cancer cells and those from normal cells, a large amount of antitumor agents acting directly on mitochondria have been researched and developed. A part of these agents trigger mitochondria-mediated apoptosis via inhibition of Bcl-2/Bcl-xL or activation of Bax/Bak, leading to protein permeable channel formation on the outer mitochondrial membrane to strengthen the release of proapoptotic factors (Fantin and Leder, 2006; Brahmbhatt et al., 2015), which is a key event in intrinsic apoptosis initiation. Another part of these antitumor agents act directly on PTPC compo-nents such as 13(S)-HODE nucleotide translocator (ANT), CypD and VDAC, resulting ultimately in the cracking of mitochondrial membrane and the release of proapoptotic factors (Dalla et al., 2014). Excitingly, the above
    Corresponding author.
    Correspondence to: Department of Pharmacy, Zhengzhou University People's Hospital, No. 7, Weiwu Road, Zhengzhou, Henan 450003, China. E-mail addresses: [email protected] (H.-M. Liu), [email protected] (A.-F. Wang). 1 Yong-Cheng Ma and Ying-Li Zhu contribute equally to this work.
    methods exhibited great benefits in animals and humans bearing tu-mors, including mice with xenograft tumor, as well as patients with tumor (Vyas et al., 2016; Sehrawat et al., 2017).
    The ent-kaurane diterpenoids are a group of compounds isolated from the genus Isodon. These diterpenoids have attracted increasing attention due to their unique and extensive pharmacological activities, especially anticancer activity (Ding et al., 2016; Liu et al., 2017). It was reported that these diterpenoids had an excellent anti-tumor effect in various cancer models, including esophageal cancer, gastric cancer, breast cancer, and so on (Liu et al., 2017; Wang et al., 2011). The an-ticancer activity of these compounds is related to the rupture of mi-tochondria, such as MMP decrease, release of cytochrome c and caspase cascade activation. Particularly, it was reported recently that oridonin, a representative compound among ent-kaurane diterpenoids, was ra-pidly taken up into tumor cells and localized in the mitochondria (Xu et al., 2016). Our previous results have also shown that Jaridonin, a nature ent-kaurane diterpenoid extracted from Isodon rubescens in Jiyuan city (Ma et al., 2013), and its derivative DS2 trigger mi-tochondria-mediated apoptosis in human esophageal cancer cell lines (Ma et al., 2016).
    Importantly, based on the scaffold of Jaridonin, efficient synthetic methods were presently established by our group to find a series of triazole-fused Jaridonin derivatives with enhanced anticancer activity and unique pharmacological mechanism. As previously reported in literature, the 1,2,3-triazole scaffold is a typical pharmacophore, which can readily bind to biological targets through hydrogen bonds and di-pole interactions (Dalvie et al., 2002; Agalave et al., 2011). The triazole derivatives are relatively stable to metabolic degradation and capable of providing target binding and cell permeability improvement (Ding et al., 2013). In this study, we evaluated the antitumor activity in vitro/ in vivo, mitochondrial toxicity and molecular mechanism of DN3, a typical triazole-substituted Jaridonin analog, in gastric cancer cells. The synthetic procedures and the structure identification of DN3 are shown in Supplementary Figs. The results firstly showed that DN3 selectively inhibited gastric cancer cell lines growth in a PTPC-mediated me-chanism. More interestingly, DN3 perturbed directly mitochondria isolated from gastric cancer cells but not those isolated from normal gastric epithelial cells. Finally, we confirmed that DN3 significantly suppressed xenograft tumor growth in vivo without affecting body weight.