Targeting the inhibitor of apoptosis proteins as a novel therapeutic strategy in medulloblastoma

Keating, Joanna, Tsoli, Maria, Hallahan, Andrew R., Ingram, Wendy J., Haber, Michelle and Ziegler, David S. (2012) Targeting the inhibitor of apoptosis proteins as a novel therapeutic strategy in medulloblastoma. Molecular Cancer Therapeutics, 11 12: 2654-2663. doi:10.1158/1535-7163.MCT-12-0352


Author Keating, Joanna
Tsoli, Maria
Hallahan, Andrew R.
Ingram, Wendy J.
Haber, Michelle
Ziegler, David S.
Title Targeting the inhibitor of apoptosis proteins as a novel therapeutic strategy in medulloblastoma
Journal name Molecular Cancer Therapeutics   Check publisher's open access policy
ISSN 1535-7163
1538-8514
Publication date 2012-12
Sub-type Article (original research)
DOI 10.1158/1535-7163.MCT-12-0352
Volume 11
Issue 12
Start page 2654
End page 2663
Total pages 10
Place of publication Philadelphia, United States
Publisher American Association for Cancer Research
Collection year 2013
Language eng
Formatted abstract
Medulloblastoma is the most common malignant brain tumor of childhood. Novel therapeutic strategies are urgently needed to overcome cytotoxic resistance. We hypothesized that antiapoptotic signals contribute to resistance and that treatment with proapoptotic agents could increase the efficacy of conventional therapies. A PCR array was used to assess the status of the apoptotic signaling pathway in medulloblastoma cells after treatment with cytotoxic chemotherapy. Treatment with cisplatin led to the upregulation of antiapoptotic signals, including inhibitor of apoptosis proteins (IAP), in medulloblastoma cells. We subsequently investigated the synergistic effect of a small-molecule IAP inhibitor, LBW242, in combination with cisplatin and/or radiotherapy in three human medulloblastoma cell lines and 5 short term primary patient medulloblastoma cultures. The addition of LBW242 to chemotherapy resulted in significantly increased antitumor activity with a similar effect observed in combination with radiotherapy. Measurement of caspase-8 and -9 activity indicated that the synergy resulted from induction of both the intrinsic and extrinsic apoptotic pathways. Apoptosis was confirmed by Annexin V staining and activation of caspases 3/7. Xenograft models were used to evaluate the mechanism of action and efficacy in vivo. The combination therapy significantly reduced the tumor burden in a medulloblastoma xenograft model and TUNEL analysis in a medulloblastoma orthograft confirmed in vivo induction of apoptosis. These findings support the strategy of targeting IAPs in combination with cytotoxic therapy as a novel treatment strategy for patients with medulloblastoma.
Keyword Sonic Hedgehog
In-Vivo
Cancer
Cells
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Faculty of Health and Behavioural Sciences -- Publications
Official 2013 Collection
School of Medicine Publications
 
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