Smac mimetic LBW242 sensitizes XIAP-overexpressing neuroblastoma cells for TNF-α-independent apoptosis.
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Smac mimetic LBW242 sensitizes XIAP-overexpressing neuroblastoma cells for TNF-α-independent apoptosis. / Eschenburg, Georg; Eggert, Angelika; Schramm, Alexander; Lode, Holger N; Hundsdoerfer, Patrick.
In: CANCER RES, Vol. 72, No. 10, 10, 2012, p. 2645-2656.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Smac mimetic LBW242 sensitizes XIAP-overexpressing neuroblastoma cells for TNF-α-independent apoptosis.
AU - Eschenburg, Georg
AU - Eggert, Angelika
AU - Schramm, Alexander
AU - Lode, Holger N
AU - Hundsdoerfer, Patrick
PY - 2012
Y1 - 2012
N2 - 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-?-induced apoptosis by degradation of cellular IAP (cIAP)-1/2, we found that LBW242-mediated sensitization in neuroblastoma cells occurred in a TNF-?-independent manner, despite induction of cIAP-1/2 degradation and TNF-? expression. Together, our findings show that XIAP targeting sensitizes neuroblastoma to chemotherapy-induced apoptosis, suggesting a novel therapeutic approach to treat this childhood malignancy.
AB - 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-?-induced apoptosis by degradation of cellular IAP (cIAP)-1/2, we found that LBW242-mediated sensitization in neuroblastoma cells occurred in a TNF-?-independent manner, despite induction of cIAP-1/2 degradation and TNF-? expression. Together, our findings show that XIAP targeting sensitizes neuroblastoma to chemotherapy-induced apoptosis, suggesting a novel therapeutic approach to treat this childhood malignancy.
KW - Animals
KW - Humans
KW - Female
KW - Mice
KW - Up-Regulation
KW - Apoptosis
KW - Cell Line, Tumor
KW - Tumor Necrosis Factor-alpha/metabolism
KW - Molecular Targeted Therapy
KW - Antineoplastic Agents/therapeutic use
KW - Antineoplastic Agents, Hormonal/therapeutic use
KW - Neuroblastoma/drug therapy/metabolism
KW - Oligopeptides/pharmacology/therapeutic use
KW - X-Linked Inhibitor of Apoptosis Protein/metabolism
KW - Animals
KW - Humans
KW - Female
KW - Mice
KW - Up-Regulation
KW - Apoptosis
KW - Cell Line, Tumor
KW - Tumor Necrosis Factor-alpha/metabolism
KW - Molecular Targeted Therapy
KW - Antineoplastic Agents/therapeutic use
KW - Antineoplastic Agents, Hormonal/therapeutic use
KW - Neuroblastoma/drug therapy/metabolism
KW - Oligopeptides/pharmacology/therapeutic use
KW - X-Linked Inhibitor of Apoptosis Protein/metabolism
M3 - SCORING: Journal article
VL - 72
SP - 2645
EP - 2656
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 10
M1 - 10
ER -
