Document Detail

Epothilone B confers radiation dose enhancement in DAB2IP gene knock-down radioresistant prostate cancer cells.
MedLine Citation:
PMID:  20970033     Owner:  NLM     Status:  MEDLINE    
PURPOSE: In metastatic prostate cancer, DOC-2/DAB2 interactive protein (DAB2IP) is often downregulated and has been reported as a possible prognostic marker to predict the risk of aggressive prostate cancer (PCa). Our preliminary results show that DAB2IP-deficient PCa cells are radioresistant. In this study, we investigated the anticancer drug Epothilone B (EpoB) for the modulation of radiosensitivity in DAB2IP-deficient human PCa cells. METHODS AND MATERIALS: We used a stable DAB2IP-knock down human PCa cell line, PC3 shDAB2IP, treated with EpoB, ionizing radiation (IR), or the combined treatment of EpoB and IR. The modulation of radiosensitivity was determined by surviving fraction, cell cycle distribution, apoptosis, and DNA double-strand break (DSB) repair. For in vivo studies, the PC3shDAB2IP xenograft model was used in athymic nude mice. RESULTS: Treatment with EpoB at IC(50) dose (33.3 nM) increased cellular radiosensitivity in the DAB2IP-deficient cell line with a dose enhancement ratio of 2.36. EpoB delayed the DSB repair kinetics after IR and augmented the induction of apoptosis in irradiated cells after G(2)/M arrest. Combined treatment of EpoB and radiation enhanced tumor growth delay with an enhancement factor of 1.2. CONCLUSIONS: We have demonstrated a significant radiation dose enhancement using EpoB in DAB2IP-deficient prostate cancer cells. This radiosensitization can be attributed to delayed DSB repair, prolonged G(2) block, and increased apoptosis in cells entering the cell cycle after G(2)/M arrest.
Zhaolu Kong; Pavithra Raghavan; Daxing Xie; Thomas Boike; Sandeep Burma; David Chen; Arup Chakraborty; Jer-Tsong Hsieh; Debabrata Saha
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  International journal of radiation oncology, biology, physics     Volume:  78     ISSN:  1879-355X     ISO Abbreviation:  Int. J. Radiat. Oncol. Biol. Phys.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-10-25     Completed Date:  2010-11-10     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7603616     Medline TA:  Int J Radiat Oncol Biol Phys     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1210-8     Citation Subset:  IM    
Copyright Information:
Copyright © 2010. Published by Elsevier Inc.
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9187, USA.
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MeSH Terms
Antineoplastic Agents / therapeutic use*
Apoptosis / drug effects
Cell Line, Tumor
Combined Modality Therapy / methods
DNA Breaks, Double-Stranded
DNA Repair
Epothilones / therapeutic use*
G2 Phase
Gene Knockdown Techniques
Mice, Nude
Neoplasm Proteins / deficiency,  genetics*
Prostatic Neoplasms / genetics,  radiotherapy*
Radiation Tolerance / drug effects*,  genetics
Radiation-Sensitizing Agents / therapeutic use
Xenograft Model Antitumor Assays
ras GTPase-Activating Proteins / deficiency,  genetics*
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents; 0/DAB2IP protein, human; 0/Epothilones; 0/Neoplasm Proteins; 0/Radiation-Sensitizing Agents; 0/epothilone B; 0/ras GTPase-Activating Proteins

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