Abstract
BackgroundMedulloblastoma (MB) is the most common pediatric primary malignant brain tumor. Approximately one-third of MB patients succumb to treatment failure and some survivors suffer detrimental side effects. Hence, the purpose of this study is to explore new therapeutic regimens to overcome chemotherapeutic agent resistance or reduce chemotherapy-induced toxicity.MethodsWe detected the expression of inhibitors of apoptosis proteins (IAPs) in MB and CD133+ MB cell lines and MB tissues using immunoblotting and immunohistochemical staining. The antitumor effects of inhibitors against IAPs on MB or CD133+ MB cells were evaluated by MTT assay, Annexin V/PI analysis, and caspase-3/7 activity. Autophagy was assessed by the conversion of light chain (LC) 3-I to LC3-II and Cyto-ID autophagy detection kit.ResultsMB cells showed higher expression of IAPs compared to normal astrocytes and normal brain tissues. Conventional chemotherapeutic agents combined with small-molecule IAP inhibitors (LCL161 or LBW242) showed a synergistic effect in MB cells. Combined treatments triggered apoptosis in MB cells through activation of caspase-3/7 and autophagic flux simultaneously. In addition, we found that CD133+ MB cells with features of cancer stem cells displayed higher levels of X-linked inhibitor of apoptosis (XIAP) and cellular inhibitor of apoptosis 1/2 (cIAP1/2), and were hypersensitive to treatment with IAP inhibitors.ConclusionsThese results shed light on the biological effects of combination therapy on MB cells and illustrate that IAP inhibitors are more effective for CD133+ stem-like MB cells.
Highlights
Medulloblastoma (MB), an embryonic tumor of the cerebellum, is the most common malignant childhood brain tumor, comprising 15–30% of intracranial tumors in the pediatric population [1] with a peak incidence of 3–9 years of age [2]
Conventional chemotherapeutic agents combined with small-molecule inhibitors of apoptosis proteins (IAPs) inhibitors (LCL161 or LBW242) showed a synergistic effect in MB cells
High expression of IAPs appears in human MB tissues and cell lines To verify whether MB tumors and cell lines have higher levels of IAPs, we determined X-linked inhibitor of apoptosis (XIAP) and cellular inhibitor of apoptosis 1/2 (cIAP1/2) levels using immunoblotting
Summary
Medulloblastoma (MB), an embryonic tumor of the cerebellum, is the most common malignant childhood brain tumor, comprising 15–30% of intracranial tumors in the pediatric population [1] with a peak incidence of 3–9 years of age [2]. Developing new effective therapeutic regimens, which can prolong survival and reduce the impact of chemodrug-induced toxicity, is critical for MB patients. Over the past two decades, the conventional chemotherapeutic agents for treating MB patients include vincristine and cisplatin [7,8,9,10] These drugs have harmful side effects and give rise to resistance. The purpose of this study is to explore new therapeutic regimens to overcome chemotherapeutic agent resistance or reduce chemotherapyinduced toxicity
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