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A small-molecule IAP inhibitor overcomes resistance to cytotoxic therapies in malignant gliomas in vitro and in vivo.

Abstract
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.
AuthorsDavid 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
JournalNeuro-oncology (Neuro Oncol) Vol. 13 Issue 8 Pg. 820-9 (Aug 2011) ISSN: 1523-5866 [Electronic] England
PMID21724651 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Inhibitor of Apoptosis Proteins
  • LBW242
  • Oligopeptides
  • Radiation-Sensitizing Agents
  • Dacarbazine
  • Temozolomide
Topics
  • Animals
  • 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)
  • Humans
  • In Vitro Techniques
  • Inhibitor of Apoptosis Proteins (antagonists & inhibitors, metabolism)
  • Mice
  • Mice, Nude
  • Oligopeptides (therapeutic use)
  • Radiation-Sensitizing Agents (therapeutic use)
  • Temozolomide
  • Xenograft Model Antitumor Assays

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