Document Detail

Hypoxia induced resistance to doxorubicin in prostate cancer cells is inhibited by low concentrations of glyceryl trinitrate.
MedLine Citation:
PMID:  12913759     Owner:  NLM     Status:  MEDLINE    
PURPOSE: Tumor hypoxia has been correlated with metastasis and resistance to chemotherapy. Hypoxia is also associated with human prostate cancers, which are highly resistant to chemotherapy. We hypothesized that hypoxia contributes to chemoresistance in prostate cancer cells and this hypoxia induced chemoresistance can be inhibited by low concentrations of nitric oxide (NO) mimetics. MATERIALS AND METHODS: Human PC-3 and mouse TRAMP-C2 prostatic adenocarcinoma cells were incubated in 20% or 0.5% O(2) for 12 hours with or without glyceryl trinitrate (GTN) (0.1 nM). This treatment was followed by a 1-hour incubation with doxorubicin and survival was assessed by clonogenic assays. Western blot analysis was used to measure NO synthase levels. The effect of hypoxia and GTN on cell cycle distribution was determined by flow cytometry. RESULTS: Hypoxic pre-incubation of the 2 cell lines resulted in increased survival following exposure to doxorubicin. Co-incubation of PC-3 and TRAMP-C2 cells with GTN (0.1 nM) inhibited the hypoxia induced resistance to doxorubicin. Each cell line expressed all 3 NO synthase isoforms at levels that were not significantly affected by O(2) concentrations. Cell cycle analysis revealed that there was no significant difference in the distribution of PC-3 cells at each stage of the cycle. However, incubation under hypoxia resulted in a small decrease in the number of TRAMP-C2 cells in S-phase. CONCLUSIONS: These findings indicate that NO may have an important role in the regulation of chemosensitivity in prostate cancer cells. Furthermore, the results suggest that GTN administration may represent a means of chemosensitizing prostatic carcinomas.
Lisa J Frederiksen; D Robert Siemens; Jeremy P Heaton; Lori R Maxwell; Michael A Adams; Charles H Graham
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  The Journal of urology     Volume:  170     ISSN:  0022-5347     ISO Abbreviation:  J. Urol.     Publication Date:  2003 Sep 
Date Detail:
Created Date:  2003-08-12     Completed Date:  2003-09-26     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0376374     Medline TA:  J Urol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1003-7     Citation Subset:  AIM; IM    
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada K7L 3N6.
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MeSH Terms
Adenocarcinoma / physiopathology*
Blotting, Western
Cell Cycle
Doxorubicin / therapeutic use*
Drug Resistance, Neoplasm / physiology*
Flow Cytometry
Nitric Oxide / physiology*
Nitric Oxide Synthase / analysis
Nitroglycerin / pharmacology*
Prostatic Neoplasms / physiopathology*
Vasodilator Agents / pharmacology*
Reg. No./Substance:
0/Vasodilator Agents; 10102-43-9/Nitric Oxide; 23214-92-8/Doxorubicin; 55-63-0/Nitroglycerin; EC Oxide Synthase

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