title: Bisacodyl and its cytotoxic activity on human glioblastoma stem-like cells. Implication of inositol 1,4,5-triphosphate receptor dependent calcium signaling.
abstract: Glioblastoma is the most common malignant brain tumor. The heterogeneity at the cellular level, metabolic specificities and plasticity of the cancer cells are a challenge for glioblastoma treatment. Identification of cancer cells endowed with stem properties and able to propagate the tumor in animal xenografts has opened a new paradigm in cancer therapy. Thus, to increase efficacy and avoid tumor recurrence, therapies need to target not only the differentiated cells of the tumor mass, but also the cancer stem-like cells. These therapies need to be effective on cells present in the hypoxic, slightly acidic microenvironment found within tumors. Such a microenvironment is known to favor more aggressive undifferentiated phenotypes and a slow-growing "quiescent state" that preserves the cells from chemotherapeutic agents, which mostly target proliferating cells. Based on these considerations, we performed a differential screening of the Prestwick Chemical Library of approved drugs on both proliferating and quiescent glioblastoma stem-like cells and identified bisacodyl as a cytotoxic agent with selectivity for quiescent glioblastoma stem-like cells. In the present study we further characterize bisacodyl activity and show its efficacy in vitro on clonal macro-tumorospheres, as well as in vivo in glioblastoma mouse models. Our work further suggests that bisacodyl acts through inhibition of Ca2+release from the InsP3 receptors.
authors.affiliation: Laboratoire d'Excellence Medalis, Université de Strasbourg, CNRS, LIT UMR 7200, F-67000 Strasbourg, France.
authors.forename: Jihu
authors.initials: J
authors.lastname: Dong
authors.affiliation: Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 118 route de Narbonne, F-31062 Toulouse Cedex, France.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Aulestia
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Department of Neurosurgery, Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital Stanford University, California, USA.
authors.forename: Suzana
authors.initials: S
authors.lastname: Assad Kahn
authors.affiliation: Laboratoire d'Excellence Medalis, Université de Strasbourg, CNRS, LIT UMR 7200, F-67000 Strasbourg, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Zeniou
authors.affiliation: CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005 Paris, France.
authors.forename: Luiz Gustavo
authors.initials: LG
authors.lastname: Dubois
authors.affiliation: CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005 Paris, France.
authors.forename: Elias A
authors.initials: EA
authors.lastname: El-Habr
authors.affiliation: Laboratoire d'Excellence Medalis, Université de Strasbourg, CNRS, LIT UMR 7200, F-67000 Strasbourg, France.
authors.forename: François
authors.initials: F
authors.lastname: Daubeuf
authors.affiliation: Laboratoire d'Excellence Medalis, Université de Strasbourg, CNRS, LIT UMR 7200, F-67000 Strasbourg, France.
authors.forename: Nassera
authors.initials: N
authors.lastname: Tounsi
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Department of Neurosurgery, Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital Stanford University, California, USA.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Cheshier
authors.affiliation: Laboratoire d'Excellence Medalis, Université de Strasbourg, CNRS, LIT UMR 7200, F-67000 Strasbourg, France.
authors.forename: Nelly
authors.initials: N
authors.lastname: Frossard
authors.affiliation: CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005 Paris, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Junier
authors.affiliation: CNRS UMR8246, Inserm U1130, UPMC, Neuroscience Paris Seine-IBPS, Sorbonne Universities, 75005 Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Chneiweiss
authors.affiliation: Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 118 route de Narbonne, F-31062 Toulouse Cedex, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Néant
authors.affiliation: Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 118 route de Narbonne, F-31062 Toulouse Cedex, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Moreau
authors.affiliation: Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 118 route de Narbonne, F-31062 Toulouse Cedex, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Leclerc
authors.affiliation: Laboratoire d'Excellence Medalis, Université de Strasbourg, CNRS, LIT UMR 7200, F-67000 Strasbourg, France. Electronic address: haiech@unistra.fr.
authors.forename: Jacques
authors.initials: J
authors.lastname: Haiech
authors.affiliation: Laboratoire d'Excellence Medalis, Université de Strasbourg, CNRS, LIT UMR 7200, F-67000 Strasbourg, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Kilhoffer
mesh_terms: D001726:Bisacodyl / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D001726:Bisacodyl
keywords: Bisacodyl; Calcium; Cancer stem-like cells; Glioblastoma; InsP3R; Macro-tumorospheres