GDC-0152 induces apoptosis through down-regulation of IAPs in human leukemia cells and inhibition of PI3K/Akt signaling pathway

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• 作者：Rong Hu (1)
  Jia Li (1)
  Zhuogang Liu (1)
  Miao Miao (1)
  Kun Yao (1)
  
  1. Department of Hematology ; Shengjing Hospital ; China Medical University ; Shenyang ; 110004 ; China
  
• 关键词：GDC ; 0152 ; IAPs ; Leukemia ; PI3K/Akt signaling pathway
• 刊名：Tumor Biology
• 出版年：2015
• 出版时间：February 2015
• 年：2015
• 卷：36
• 期：2
• 页码：577-584
• 全文大小：2,264 KB
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• 刊物主题：Cancer Research;
• 出版者：Springer Netherlands
• ISSN：1423-0380

文摘

The inhibitor of apoptosis proteins (IAPs) is closely related to leukemia apoptosis. The present study was undertaken to determine the molecular mechanisms by which GDC-0152, an IAP inhibitor, induces apoptosis in human leukemia cells (K562 and HL60 cells). GDC-0152 inhibited the proliferation of K562 and HL60 cells in a dose- and time-dependent manner, which was largely attributed to intrinsic apoptosis. GDC-0152 down-regulated the IAPs including X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein-1 (cIAP1), and cellular inhibitor of apoptosis protein-2 (cIAP2) expression and induced the activation of caspase-9 and caspase-3. GDC-0152-induced cell proliferation inhibition in K562 cells was prevented by pan-caspase inhibitor. GDC-0152 also inhibited PI3K and Akt expression in K562 and HL60 cells. Taken together, these findings suggest that GDC-0152 results in human leukemia apoptosis through caspase-dependent mechanisms involving down-regulation of IAPs and inhibition of PI3K/Akt signaling.