Department of Biotechnology and Bioengineering, Izmir Institute of Technology, 35430, Urla, Izmir, Turkey.
Izmir Biomedicine and Genome Center, 35340, Balcova, Izmir, Turkey; Department of Medical Biology and Genetics, Faculty of Medicine, Dokuz Eylul University, 35340, Balcova, Izmir, Turkey.
Eur J Med Chem. 2019 Oct 15;180:224-237. doi: 10.1016/j.ejmech.2019.07.024. Epub 2019 Jul 9.
Cytotoxic effects of (R)-4'-methylklavuzon were investigated on hepatocellular carcinoma cells (HuH-7 and HepG2) and HuH-7 EpCAM/CD133 cancer stem cells. IC of (R)-4'-methylklavuzon was found as 1.25 μM for HuH-7 parental cells while it was found as 2.50 μM for HuH-7 EpCAM/CD133 cancer stem cells. (R)-4'-methylklavuzon tended to show more efficient in vitro cytotoxicity with its lower IC values on hepatocellular carcinoma cell lines compared to its lead molecule, goniothalamin and FDA-approved drugs, sorafenib and regorafenib. Cell-based Sirtuin/HDAC enzyme activity measurements revealed that endogenous Sirtuin/HDAC enzymes were reduced by 40% compared to control. SIRT1 protein levels were upregulated indicating triggered DNA repair mechanism. p53 was overexpressed in HepG2 cells. (R)-4'-methylklavuzon inhibited CRM1 protein providing increased retention of p53 and RIOK2 protein in the nucleus. HuH-7 parental and EpCAM/CD133 cancer stem cell spheroids lost intact morphology. 3D HepG2 spheroid viabilities were decreased in a correlation with upregulation in p53 protein levels.
（R）-4'-甲基克拉维酮对肝癌细胞（HuH-7 和 HepG2）和 HuH-7 EpCAM/CD133 癌症干细胞的细胞毒性作用进行了研究。（R）-4'-甲基克拉维酮对 HuH-7 亲本细胞的 IC 为 1.25 μM，而对 HuH-7 EpCAM/CD133 癌症干细胞的 IC 为 2.50 μM。与先导分子戈尼辛和 FDA 批准的药物索拉非尼和regorafenib 相比，（R）-4'-甲基克拉维酮在肝癌细胞系中的体外细胞毒性作用更为有效，其 IC 值较低。基于细胞的 Sirtuin/HDAC 酶活性测量显示，与对照组相比，内源性 Sirtuin/HDAC 酶减少了 40%。SIRT1 蛋白水平上调表明触发了 DNA 修复机制。p53 在 HepG2 细胞中过表达。（R）-4'-甲基克拉维酮抑制 CRM1 蛋白，从而增加 p53 和 RIOK2 蛋白在核内的保留。HuH-7 亲本和 EpCAM/CD133 癌症干细胞球体失去完整形态。3D HepG2 球体的活力与 p53 蛋白水平的上调呈正相关。
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