Smac mimetic LBW242 sensitizes XIAP-overexpressing neuroblastoma cells for TNF-α-independent apoptosis.

Abstract

Despite intensive treatment regimens, high-risk and late-stage neuroblastoma tends to have a poor survival outcome. Overexpression of the apoptotic regulator, X-linked inhibitor of apoptosis protein (XIAP), has been associated with chemotherapy resistance in several cancers including neuroblastoma. Here, we report preclinical evidence that XIAP offers an effective therapeutic target in neuroblastoma. Human and murine neuroblastoma cells were treated with the Smac mimetic LBW242 alone or in combination with cytotoxic drugs used clinically to treat neuroblastoma. Expression of XIAP protein, but not mRNA, was highly increased in neuroblastoma cells compared to healthy adrenal gland tissue, consistent with a posttranscriptional regulation of XIAP expression. Treatment with LBW242 sensitized human and murine neuroblastoma cells to chemotherapy-induced apoptosis, which was mediated by activation of both the intrinsic and extrinsic apoptosis pathways. Although Smac mimetics have been reported to stimulate TNF-α-induced apoptosis by degradation of cellular IAP (cIAP)-1/2, we found that LBW242-mediated sensitization in neuroblastoma cells occurred in a TNF-α-independent manner, despite induction of cIAP-1/2 degradation and TNF-α expression. Together, our findings show that XIAP targeting sensitizes neuroblastoma to chemotherapy-induced apoptosis, suggesting a novel therapeutic approach to treat this childhood malignancy.

• Authors: Georg Eschenburg, Angelika Eggert, Alexander Schramm, Holger N Lode, Patrick Hundsdoerfer
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 10 Pg. 2645-56 (May 15 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22491673 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Antineoplastic Agents
• Antineoplastic Agents, Hormonal
• LBW242
• Oligopeptides
• Tumor Necrosis Factor-alpha
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Agents, Hormonal (therapeutic use)
• Apoptosis
• Cell Line, Tumor
• Female
• Humans
• Mice
• Molecular Targeted Therapy
• Neuroblastoma (drug therapy, metabolism)
• Oligopeptides (pharmacology, therapeutic use)
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation
• X-Linked Inhibitor of Apoptosis Protein (metabolism)