Selective Release of a Cyclopamine Glucuronide Prodrug toward Stem-like Cancer Cell Inhibition in Glioblastoma

Anais Balbous (1, 2, 3) , Brigitte Renoux (4) , Ulrich Cortes (1, 2, 3) , Serge Milin (5) , Karline Guilloteau (1) , Thibaut Legigan (4) , Pierre Rivet (1) , Odile Boissonnade (5) , Sébastien Martin (1) , Caroline Tripiana (5) , Michel Wager (1) , René-Jean Bensadoun (5) , Sebastien Papot (4) , Lucie Karayan-Tapon (1)

1 Cellules souches leucémiques et thérapeuthiques
2 ONCOSTEM - Modèles de Cellules Souches Malignes et Thérapeutiques
3 Laboratoire Cancérologie Biologique Poitiers
4 IC2MP [Poitiers] - Institut de chimie des milieux et matériaux de Poitiers [UMR 7285]
5 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital

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 beta-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 mu mol/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

Domaines: Catalyse

Anais Balbous, Brigitte Renoux, Ulrich Cortes, Serge Milin, Karline Guilloteau, et al.. Selective Release of a Cyclopamine Glucuronide Prodrug toward Stem-like Cancer Cell Inhibition in Glioblastoma. Molecular Cancer Therapeutics, 2014, 13 (9), pp.2159-2169. ⟨10.1158/1535-7163.MCT-13-1038⟩. ⟨hal-01313891⟩