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

Delman M., Avci S. T., Akcok I., Kanbur T., Erdal E., Cagir A.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, cilt.180, ss.224-237, 2019 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 180
  • Basım Tarihi: 2019
  • Doi Numarası: 10.1016/j.ejmech.2019.07.024
  • Dergi Adı: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.224-237
  • Anahtar Kelimeler: Hepatocellular carcinoma, Cancer stem cell, SIRT1 inhibitor, CRM1 inhibitor, Topoisomerase I inhibitor, Klavuzon, IN-VITRO, NUCLEAR TRANSPORT, DRUG-RESISTANCE, GONIOTHALAMIN, P53, APOPTOSIS, ANTICANCER, ACTIVATION, MECHANISM, EXPRESSION
  • Dokuz Eylül Üniversitesi Adresli: Evet

Özet

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 mu M for HuH-7 parental cells while it was found as 2.50 mu M 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. (C) 2019 Elsevier Masson SAS. All rights reserved.