title: Selective anticancer effects of a synthetic flavagline on human Oct4-expressing cancer stem-like cells via a p38 MAPK-dependent caspase-3-dependent pathway.
abstract: Cancer stem cells (CSCs) are considered as the initiators of the carcinogenic process and are therefore emerging targets for innovative anticancer therapies. In order to evaluate the anticancer chemopreventive activity of flavagline derivatives, we used the pluripotent teratocarcinomal cell as a model of Oct4-expressing cancer stem-like cell and determined the underlying cellular and molecular mechanisms induced by a synthetic flavagline. We precisely investigated the effects of the flavagline derivative FL3 on the human embryonal carcinoma (EC) cell line NT2/D1 and compared the responses to those of a normal more restrictive pluripotent stem cell line (i.e. BJ fibroblast cell line). FL3 selectively inhibited the proliferation of NT2/D1 cells by inducing G1 phase cell cycle arrest in a dose-dependent manner. Moreover, FL3 treatment specifically triggered apoptosis in association with an induction of the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and caspase-3 activation followed by a drastic downregulation of the master regulator of stemness Oct4. Forced inhibition of p38 MAPK activity by the specific pharmacological inhibitor SB203580 or by p38 MAPK gene knockdown using small-interfering RNA (siRNA) counteracted the effects of FL3, demonstrating that its chemopreventive action is related to growth inhibition and a p38-dependent caspase-3-dependent induction of apoptosis in Oct4-expressing CSCs. This study also shows that FL3 selectively kills poorly differentiated and highly aggressive carcinomal cells, but has little effect on normal stem-like cells. Thus FL3 offers great promise for cancer treatment since it is able to target the carcinogenic process without affecting normal cells.
authors.affiliation: UMR 7213 CNRS, Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
authors.forename: Fathi
authors.initials: F
authors.lastname: Emhemmed
authors.affiliation: UMR 7213 CNRS, Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ali Azouaou
authors.affiliation: UMR 7200 CNRS, Laboratoire d'Innovation Thérapeutique, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Thuaud
authors.affiliation: UMR 7213 CNRS, Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Schini-Kerth
authors.affiliation: UMR 7200 CNRS, Laboratoire d'Innovation Thérapeutique, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Désaubry
authors.affiliation: UMR 7200 CNRS, Laboratoire d'Innovation Thérapeutique, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Muller
authors.affiliation: UMR 7213 CNRS, Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France. Electronic address: guy.fuhrmann@unistra.fr.
authors.forename: Guy
authors.initials: G
authors.lastname: Fuhrmann
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007093:Imidazoles; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D010936:Plant Extracts; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; C093642:SB 203580
keywords: Apoptosis; Cancer stem cells; Flavagline; Oct4; Teratocarcinoma