gdc-0152 and Brain-Neoplasms

In glioblastomas, apoptosis inhibitor proteins (IAPs) are involved in apoptotic and nonapoptotic processes. We previously showed that IAP inhibition induced a loss of stemness and glioblastoma stem cells differentiation by activating nuclear factor-κB under normoxic conditions. Hypoxia has been shown to modulate drug efficacy. Here, we investigated how IAPs participate in glioblastoma stem-like cell maintenance and fate under hypoxia. We showed that in a hypoxic environment, IAPs inhibition by GDC-0152, a small-molecule IAPs inhibitor, triggered stem-like cell apoptosis and decreased proliferation in four human glioblastoma cell lines. We set up a three-dimensional glioblastoma spheroid model in which time-of-flight secondary ion mass spectrometry analyses revealed a decrease in oxygen levels between the periphery and core. We observed low proliferative and apoptotic cells located close to the hypoxic core of the spheres and glial fibrillary acidic protein

Topics: Adaptor Proteins, Signal Transducing; Adrenomedullin; Apoptosis; Baculoviral IAP Repeat-Containing 3 Protein; Brain Neoplasms; Carbonic Anhydrase IX; Cell Differentiation; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Cyclohexanes; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Inhibitor of Apoptosis Proteins; Neoplasm Proteins; Neoplastic Stem Cells; Oxygen; Pyrroles; Signal Transduction; Spheroids, Cellular; Tissue Culture Techniques; X-Linked Inhibitor of Apoptosis Protein