Blockade of Inhibitors of Apoptosis Proteins in Combination with Conventional Chemotherapy Leads to Synergistic Antitumor Activity in Medulloblastoma and Cancer Stem-Like CellsReportar como inadecuado




Blockade of Inhibitors of Apoptosis Proteins in Combination with Conventional Chemotherapy Leads to Synergistic Antitumor Activity in Medulloblastoma and Cancer Stem-Like Cells - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Background

Medulloblastoma 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.

Methods

We 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.

Results

MB 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.

Conclusions

These 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.



Autor: Shu-Mei Chen, Ying-Ying Li, Chiao-Hui Tu, Nicole Salazar, Yuan-Yun Tseng, Shiang-Fu Huang, Ling-Ling Hsieh , Tai-Ngar Lui

Fuente: http://plos.srce.hr/



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