2. Academic Validation
  3. Antiproliferative activity of (R)-4'-methylklavuzon on hepatocellular carcinoma cells and EpCAM+/CD133+ cancer stem cells via SIRT1 and Exportin-1 (CRM1) inhibition

Antiproliferative activity of (R)-4'-methylklavuzon on hepatocellular carcinoma cells and EpCAM+/CD133+ cancer stem cells via SIRT1 and Exportin-1 (CRM1) inhibition

  • Eur J Med Chem. 2019 Oct 15:180:224-237. doi: 10.1016/j.ejmech.2019.07.024.
Murat Delman 1,  Sanem Tercan Avcı 2,  İsmail Akçok 3,  Tuğçe Kanbur 3,  Esra Erdal 4,  Ali Çağır 5
Affiliations

Affiliations

  • 1 Department of Biotechnology and Bioengineering, Izmir Institute of Technology, 35430, Urla, Izmir, Turkey.
  • 2 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.
  • 3 Department of Chemistry, Faculty of Science, Izmir Institute of Technology, 35430, Urla, Izmir, Turkey.
  • 4 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. Electronic address: esra.erdal@ibg.edu.tr.
  • 5 Department of Chemistry, Faculty of Science, Izmir Institute of Technology, 35430, Urla, Izmir, Turkey. Electronic address: alicagir@iyte.edu.tr.
PMID: 31306909 DOI: 10.1016/j.ejmech.2019.07.024
Abstract

Cytotoxic effects of (R)-4'-methylklavuzon were investigated on hepatocellular carcinoma cells (HuH-7 and HepG2) and HuH-7 EpCAM+/CD133+ Cancer Stem Cells. IC50 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 IC50 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.

Keywords

CRM1 inhibitor; Cancer stem cell; Hepatocellular carcinoma; Klavuzon; SIRT1 inhibitor; Topoisomerase I inhibitor.

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