Chemical Library Screening and Structure-Function Relationship Studies Identify Bisacodyl as a Potent and Selective Cytotoxic Agent Towards Quiescent Human Glioblastoma Tumor Stem-Like Cells.
Cancer stem-like cells reside in hypoxic and slightly acidic tumor niches. Such microenvironments favor more aggressive undifferentiated phenotypes and a slow growing "quiescent state" which preserves them from chemotherapeutic agents that essentially target proliferating cells. Our objective was to identify compounds active on glioblastoma stem-like cells, including under conditions that mimick those found in vivo within this most severe and incurable form of brain malignancy. We screened the Prestwick Library to identify cytotoxic compounds towards glioblastoma stem-like cells, either in a proliferating state or in more slow-growing "quiescent" phenotype resulting from non-renewal of the culture medium in vitro. Compound effects were assessed by ATP-level determination using a cell-based assay. Twenty active molecules belonging to different pharmacological classes have thus been identified. Among those, the stimulant laxative drug bisacodyl was the sole to inhibit in a potent and specific manner the survival of quiescent glioblastoma stem-like cells. Subsequent structure-function relationship studies led to identification of 4,4'-dihydroxydiphenyl-2-pyridyl-methane (DDPM), the deacetylated form of bisacodyl, as the pharmacophore. To our knowledge, bisacodyl is currently the only known compound targeting glioblastoma cancer stem-like cells in their quiescent, more resistant state. Due to its known non-toxicity in humans, bisacodyl appears as a new potential anti-tumor agent that may, in association with classical chemotherapeutic compounds, participate in tumor eradication.
Laboratoire d'Innovation Thérapeutique, Université de Strasbourg / CNRS UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
Maria
M
Zeniou
Laboratoire d'Innovation Thérapeutique, Université de Strasbourg / CNRS UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
Marie
M
Fève
Laboratoire d'Innovation Thérapeutique, Université de Strasbourg / CNRS UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
Samir
S
Mameri
Laboratoire d'Innovation Thérapeutique, Université de Strasbourg / CNRS UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
Jihu
J
Dong
Laboratoire d'Innovation Thérapeutique, Université de Strasbourg / CNRS UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
Christophe
C
Salomé
Laboratoire d'Innovation Thérapeutique, Université de Strasbourg / CNRS UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
Wanyin
W
Chen
Neuroscience Paris Seine-IBPS, CNRS UMR 8246/ Inserm U1130/ UPMC UMCR18, 7 quai Saint Bernard, 75005 Paris, France.
Elias A
EA
El-Habr
Laboratoire d'Innovation Thérapeutique, Université de Strasbourg / CNRS UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
Fanny
F
Bousson
Laboratoire d'Innovation Thérapeutique, Université de Strasbourg / CNRS UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
Mohamadou
M
Sy
Laboratoire d'Innovation Thérapeutique, Université de Strasbourg / CNRS UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
Julie
J
Obszynski
Laboratoire d'Innovation Thérapeutique, Université de Strasbourg / CNRS UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
Alexandre
A
Boh
Plateforme de Chimie Biologie Intégrative (PCBIS), Université de Strasbourg / CNRS UMS 3286, Laboratoire d'Excellence Medalis, ESBS Pôle API-Bld Sébastien Brant, 67401 Illkirch, France.
Pascal
P
Villa
Neuroscience Paris Seine-IBPS, CNRS UMR 8246/ Inserm U1130/ UPMC UMCR18, 7 quai Saint Bernard, 75005 Paris, France.
Suzana
S
Assad Kahn
Laboratoire d'Innovation Thérapeutique, Université de Strasbourg / CNRS UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France; Plateforme de Chimie Biologie Intégrative (PCBIS), Université de Strasbourg / CNRS UMS 3286, Laboratoire d'Excellence Medalis, ESBS Pôle API-Bld Sébastien Brant, 67401 Illkirch, France.
Bruno
B
Didier
U682, Inserm, Université de Strasbourg, 3, Avenue Molière, 67200 Strasbourg, France.
Dominique
D
Bagnard
Neuroscience Paris Seine-IBPS, CNRS UMR 8246/ Inserm U1130/ UPMC UMCR18, 7 quai Saint Bernard, 75005 Paris, France.
Marie-Pierre
MP
Junier
Neuroscience Paris Seine-IBPS, CNRS UMR 8246/ Inserm U1130/ UPMC UMCR18, 7 quai Saint Bernard, 75005 Paris, France.
Hervé
H
Chneiweiss
Laboratoire d'Innovation Thérapeutique, Université de Strasbourg / CNRS UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
Jacques
J
Haiech
Laboratoire d'Innovation Thérapeutique, Université de Strasbourg / CNRS UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
Marcel
M
Hibert
Laboratoire d'Innovation Thérapeutique, Université de Strasbourg / CNRS UMR7200, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
Marie-Claude
MC
Kilhoffer
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D054852:Small Molecule Libraries / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D003603:Cytotoxins; D054852:Small Molecule Libraries