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.
Copyright © 2019 Elsevier Masson SAS. All rights reserved.
MeSH terms
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AC133 Antigen / antagonists & inhibitors*
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AC133 Antigen / metabolism
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Epithelial Cell Adhesion Molecule / antagonists & inhibitors*
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Epithelial Cell Adhesion Molecule / metabolism
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Exportin 1 Protein
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Hep G2 Cells
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Humans
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Karyopherins / antagonists & inhibitors*
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Karyopherins / metabolism
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Molecular Structure
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Naphthalenes / chemical synthesis
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Naphthalenes / chemistry
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Naphthalenes / pharmacology*
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Sirtuin 1 / antagonists & inhibitors*
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Sirtuin 1 / metabolism
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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(R)-4'-methylklavuzon
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AC133 Antigen
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Antineoplastic Agents
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EPCAM protein, human
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Epithelial Cell Adhesion Molecule
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Karyopherins
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Naphthalenes
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Receptors, Cytoplasmic and Nuclear
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SIRT1 protein, human
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Sirtuin 1