title: Selective release of a cyclopamine glucuronide prodrug toward stem-like cancer cell inhibition in glioblastoma.
abstract: Recent data suggest that inhibition of the Hedgehog pathway could be a therapeutic target for glioblastoma. Alkaloid cyclopamine inhibits Hedgehog signaling, depleting stem-like cancer cells derived from glioblastoma. However, this compound is toxic for somatic stem cells, preventing its use for clinical applications. In this study, we tested a derivatization product of cyclopamine in the form of cyclopamine glucuronide prodrug (CGP-2). This compound was used in vitro and in vivo toward glioblastoma-initiating cells (GIC). Results obtained in vitro indicate that CGP-2 is active only in the presence of β-glucuronidase, an enzyme detected in high levels in necrotic areas of glioblastomas. CGP-2 decreased proliferation and inhibited the self-renewal of all GIC lines tested. Hedgehog pathway blockade by 10 μmol/L of CGP-2 induced a 99% inhibition of clonogenicity on GICs, similar to cyclopamine treatment. Combination of CGP-2 with radiation decreased clonogenic survival in all GIC lines compared with CGP-2 alone. In a subcutaneous glioblastoma xenograft model, a two-week CGP-2 treatment prevented tumor growth with 75% inhibition at 8 weeks, and this inhibition was still significant after 14 weeks. Unlike cyclopamine, CGP-2 had no detectable toxic effects in intestinal crypts. Our study suggests that inhibition of the Hedgehog pathway with CGP-2 is more effective than conventional temozolomide adjuvant, with much lower concentrations, and seems to be an effective therapeutic strategy for targeting GICs.
authors: INSERMU935, Modèles de cellules souches malignes et thérapeutiques, Poitiers, France. Université de Poitiers, Poitiers, France. CHU de Poitiers, Laboratoire de Cancérologie Biologique, Poitiers, France.
authors: Anaïs
authors: A
authors: Balbous
authors: Université de Poitiers, UMR-CNRS 7285, Institut de Chimie des Milieux et des Matériaux, Groupe «Systèmes Moléculaires Programmés, Poitiers, France.
authors: Brigitte
authors: B
authors: Renoux
authors: INSERMU935, Modèles de cellules souches malignes et thérapeutiques, Poitiers, France. Université de Poitiers, Poitiers, France. CHU de Poitiers, Laboratoire de Cancérologie Biologique, Poitiers, France.
authors: Ulrich
authors: U
authors: Cortes
authors: CHU de Poitiers, Service d'Anatomo-cytopathologie, Poitiers, France.
authors: Serge
authors: S
authors: Milin
authors: INSERMU935, Modèles de cellules souches malignes et thérapeutiques, Poitiers, France. Université de Poitiers, Poitiers, France. CHU de Poitiers, Laboratoire de Cancérologie Biologique, Poitiers, France.
authors: Karline
authors: K
authors: Guilloteau
authors: Université de Poitiers, UMR-CNRS 7285, Institut de Chimie des Milieux et des Matériaux, Groupe «Systèmes Moléculaires Programmés, Poitiers, France.
authors: Thibaut
authors: T
authors: Legigan
authors: CHU de Poitiers, Laboratoire de Cancérologie Biologique, Poitiers, France.
authors: Pierre
authors: P
authors: Rivet
authors: CHU de Poitiers, Service d'Oncologie Radiotherapique, Poitiers, France.
authors: Odile
authors: O
authors: Boissonnade
authors: CHU de Poitiers, Laboratoire de Cancérologie Biologique, Poitiers, France.
authors: Sébastien
authors: S
authors: Martin
authors: CHU de Poitiers, Service d'Oncologie Radiotherapique, Poitiers, France.
authors: Caroline
authors: C
authors: Tripiana
authors: CHU de Poitiers, Service de Neurochirurgie, Poitiers, France.
authors: Michel
authors: M
authors: Wager
authors: CHU de Poitiers, Service d'Oncologie Radiotherapique, Poitiers, France.
authors: René Jean
authors: RJ
authors: Bensadoun
authors: Université de Poitiers, UMR-CNRS 7285, Institut de Chimie des Milieux et des Matériaux, Groupe «Systèmes Moléculaires Programmés, Poitiers, France.
authors: Sébastien
authors: S
authors: Papot
authors: INSERMU935, Modèles de cellules souches malignes et thérapeutiques, Poitiers, France. Université de Poitiers, Poitiers, France. CHU de Poitiers, Laboratoire de Cancérologie Biologique, Poitiers, France. l.karayan-tapon@chu-poitiers.fr.
authors: Lucie
authors: L
authors: Karayan-Tapon
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D020719:Glucuronides / Q000737:chemistry*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D008747:Methylcellulose / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology*; D011355:Prodrugs / Q000737:chemistry*; D014704:Veratrum Alkaloids / Q000737:chemistry*
chemical_list: D020719:Glucuronides; D053823:Hedgehog Proteins; D011355:Prodrugs; D014704:Veratrum Alkaloids; D008747:Methylcellulose; C000541:cyclopamine