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

• Published in: PloS one Vol. 11; no. 8; p. e0161299
• Main Authors: Chen, Shu-Mei, Li, Ying-Ying, Tu, Chiao-Hui, Salazar, Nicole, Tseng, Yuan-Yun, Huang, Shiang-Fu, Hsieh, Ling-Ling, Lui, Tai-Ngar
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.08.2016; Public Library of Science (PLoS)
• Subjects: Analysis; Annexin V; Anticancer properties; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Antitumor activity; Apoptosis; Apoptosis - drug effects; Astrocytes; Autophagy; Autophagy - drug effects; Biological effects; Biology and Life Sciences; Brain; Brain cancer; Brain tumors; Cancer; Cancer therapies; Caspase; Caspase 3 - metabolism; Caspase 7 - metabolism; Caspase-3; Cell death; Cell Line, Tumor; Cell Survival; Cerebellar Neoplasms - drug therapy; Chemotherapy; Cisplatin - therapeutic use; Cytotoxicity; Drug resistance; Drug Synergism; Drug therapy; Drug Therapy, Combination; Health aspects; Hospitals; Humans; IAP protein; Immunoblotting; Inhibitors; Kinases; Medicine; Medicine and Health Sciences; Medulloblastoma; Medulloblastoma - drug therapy; Neoplastic Stem Cells - drug effects; Neuroblastoma; Neurosurgery; Oligopeptides - therapeutic use; Phagocytosis; Physiological aspects; Proteins; Public health; Research and Analysis Methods; Side effects; Stem cells; Surgery; Synergistic effect; Thiazoles - therapeutic use; Tissues; Toxicity; Tumors; Vincristine - therapeutic use; XIAP protein; Taiwan; Florida; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0161299

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. 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. 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. 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.