Document Detail

A small-molecule IAP inhibitor overcomes resistance to cytotoxic therapies in malignant gliomas in vitro and in vivo.
MedLine Citation:
PMID:  21724651     Owner:  NLM     Status:  MEDLINE    
We tested the use of the small-molecule Inhibitor of Apoptosis Protein (IAP) inhibitor LBW242 in combination with the standard-of-care therapies of irradiation and temozolomide for malignant gliomas. In vitro assays demonstrated that LBW242 enhanced the cytotoxic activity of radiotherapy, and clonogenic assays showed that the combination therapy led to a synergistic anti-glioma effect in multiple cell lines. Neurosphere assays revealed that the combination of radiation and LBW242 led to a pro-apoptotic effect in these glioma-initiating cell-enriched assays, with a corresponding inhibition of primary tumor cell growth. Athymic mice bearing established human malignant glioma tumor xenografts treated with LBW242 plus radiation and temozolomide demonstrated a synergistic suppression of tumor growth. Taken together, these experiments show that the pro-apoptotic and anti-glioma effects of radiotherapy and chemotherapy can be enhanced by the addition of a small-molecule IAP inhibitor. These results are readily translatable to clinical trial and offer the potential for improved treatment outcomes for patients with glioma.
David S Ziegler; Joanna Keating; Santosh Kesari; Eva M Fast; Leigh Zawel; Naren Ramakrishna; Jessica Barnes; Mark W Kieran; Sophie E M Veldhuijzen van Zanten; Andrew L Kung
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-07-01
Journal Detail:
Title:  Neuro-oncology     Volume:  13     ISSN:  1523-5866     ISO Abbreviation:  Neuro-oncology     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-07-29     Completed Date:  2011-12-07     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  100887420     Medline TA:  Neuro Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  820-9     Citation Subset:  IM    
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
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MeSH Terms
Antineoplastic Agents / therapeutic use*
Apoptosis / drug effects,  radiation effects
Blotting, Western
Brain Neoplasms / drug therapy*,  pathology,  radiotherapy
Cell Line, Tumor
Cell Proliferation / drug effects,  radiation effects
Combined Modality Therapy
Dacarbazine / analogs & derivatives*,  therapeutic use
Gamma Rays
Glioma / drug therapy*,  pathology,  radiotherapy
Inhibitor of Apoptosis Proteins / antagonists & inhibitors*,  metabolism
Mice, Nude
Oligopeptides / therapeutic use*
Radiation-Sensitizing Agents / therapeutic use*
Xenograft Model Antitumor Assays
Reg. No./Substance:
0/Antineoplastic Agents; 0/Inhibitor of Apoptosis Proteins; 0/LBW242; 0/Oligopeptides; 0/Radiation-Sensitizing Agents; 4342-03-4/Dacarbazine; 85622-93-1/temozolomide

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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