Abstract | PURPOSE: EXPERIMENTAL DESIGN: Radiosensitization of SH-130 in human prostate cancer DU-145 cells was determined by clonogenic survival assay. Combination effect of SH-130 and ionizing radiation was evaluated by apoptosis assays. Pull-down and immunoprecipitation assays were employed to investigate the interaction between SH-130 and IAPs. DU-145 xenografts in nude mice were treated with SH-130, radiation, or combination, and tumor suppression effect was determined by caliper measurement or bioluminescence imaging. Nuclear factor-kappaB activation was detected by luciferase reporter assay and quantitative real-time PCR. RESULTS:
SH-130 potently enhanced radiation-induced caspase activation and apoptosis in DU-145 cells. Both X-linked IAP and cIAP-1 can be pulled down by SH-130 but not by inactive SH-123. Moreover, SH-130 interrupted interaction between X-linked IAP/cIAP-1 and Smac. In a nude mouse xenograft model, SH-130 potently sensitized the DU-145 tumors to X-ray radiation without increasing systemic toxicity. The combination therapy suppressed tumor growth more significantly than either treatment alone, with over 80% of complete tumor regression. Furthermore, SH-130 partially blocked tumor necrosis factor-alpha- and radiation-induced nuclear factor-kappaB activation in DU-145 cells. CONCLUSIONS: Our results show that small-molecule inhibitors of IAPs can overcome apoptosis resistance and radiosensitize human prostate cancer with high levels of IAPs. Molecular modulation of IAPs may improve the outcome of prostate cancer radiotherapy.
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Authors | Yao Dai, Meilan Liu, Wenhua Tang, Jeffrey DeSano, Ezra Burstein, Mary Davis, Kenneth Pienta, Theodore Lawrence, Liang Xu |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 14
Issue 23
Pg. 7701-10
(Dec 01 2008)
ISSN: 1078-0432 [Print] United States |
PMID | 19047096
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Inhibitor of Apoptosis Proteins
- NF-kappa B
- Oligopeptides
- Radiation-Sensitizing Agents
- SH-130
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Topics |
- Animals
- Apoptosis
(drug effects, radiation effects)
- Blotting, Western
- Cell Line, Tumor
- Combined Modality Therapy
- Female
- Humans
- Immunoprecipitation
- Inhibitor of Apoptosis Proteins
(antagonists & inhibitors, drug effects, metabolism)
- Male
- Mice
- NF-kappa B
(drug effects, radiation effects)
- Oligopeptides
(pharmacology)
- Prostatic Neoplasms
(therapy)
- Radiation-Sensitizing Agents
(pharmacology)
- Radiotherapy
- Reverse Transcriptase Polymerase Chain Reaction
- Xenograft Model Antitumor Assays
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