1. Selective release of a cyclopamine glucuronide prodrug toward stem-like cancer cell inhibition in glioblastoma.
- Author
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Balbous A, Renoux B, Cortes U, Milin S, Guilloteau K, Legigan T, Rivet P, Boissonnade O, Martin S, Tripiana C, Wager M, Bensadoun RJ, Papot S, and Karayan-Tapon L
- Subjects
- Animals, Brain Neoplasms drug therapy, Cell Line, Tumor, Cell Proliferation, Cell Survival, Drug Design, Drug Screening Assays, Antitumor, Female, Hedgehog Proteins antagonists & inhibitors, Humans, Inhibitory Concentration 50, Methylcellulose chemistry, Mice, Mice, Nude, Neoplasm Transplantation, Glioblastoma drug therapy, Glucuronides chemistry, Neoplastic Stem Cells cytology, Prodrugs chemistry, Veratrum Alkaloids chemistry
- 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., (©2014 American Association for Cancer Research.)
- Published
- 2014
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