title: Selective ROS-dependent p53-associated anticancer effects of the hypoxoside derivative rooperol on human teratocarcinomal cancer stem-like cells.
abstract: Cancer stem cells (CSCs) are potential targets for innovative anticancer therapies that involve natural products with potential chemopreventive effects. We therefore analyzed the antineoplastic activity of rooperol, the aglycone of the plant-derived compound hypoxoside, on a model of Oct4-expressing cancer stem-like cell, i.e. the human embryonal carcinoma (EC) cell NT2/D1. Rooperol selectively inhibited the proliferation of NT2/D1 cells in a concentration-dependent manner and had no effect on either normal embryonic fibroblasts which are more restrictive pluripotent stem cells or on NCCIT p53-mutant EC cells. Accordingly, rooperol only eliminates colon carcinoma cells expressing p53. Rooperol treatment triggered cell death on NT2/D1 cells through the alteration of mitochondrial membrane potential and production of reactive oxygen species (ROS). Rooperol-induced apoptosis was associated with activation of p53 and concentration-dependent changes of the expression levels of both caspase 3 and poly ADP ribose polymerase type 1 cleaved subunits. These modifications were accompanied by a downregulation of Oct4 and its two partners involved in the maintenance of cell pluripotency and self-renewal, Nanog and Sox2.Treatment with intracellular membrane permeant O2 (-) scavengers prevented rooperol-induced apoptosis and upregulation of the expression of p53 and active caspase-3. Our findings indicate that rooperol mediates its growth inhibitory effects on CSCs via a mitochondrial redox-sensitive mechanism. We propose that abrogating the expression of the stemness regulators is a prerequisite for rooperol to fully exert its pro-apoptotic properties on wild-type p53-bearing CSCs.
authors.affiliation: UMR 7213 CNRS, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, 74 route du Rhin, 67401, Illkirch, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ali Azouaou
authors.forename: Fathi
authors.initials: F
authors.lastname: Emhemmed
authors.forename: Noureddine
authors.initials: N
authors.lastname: Idris-Khodja
authors.forename: Annelise
authors.initials: A
authors.lastname: Lobstein
authors.forename: Valérie
authors.initials: V
authors.lastname: Schini-Kerth
authors.forename: Christian D
authors.initials: CD
authors.lastname: Muller
authors.forename: Guy
authors.initials: G
authors.lastname: Fuhrmann
mesh_terms: D000480:Alkynes; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002396:Catechols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054278:Embryonal Carcinoma Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005960:Glucosides; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018243:Teratocarcinoma; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000480:Alkynes; D000970:Antineoplastic Agents; D002396:Catechols; D005960:Glucosides; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C087941:hypoxoside; C079659:rooperol; D053148:Caspase 3