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Ethanol promotes cytotoxic effects of tumor necrosis factor-related apoptosis-inducing ligand through induction of reactive oxygen species in prostate cancer cells.
MedLine Citation:
PMID:  22986577     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Background:Effective treatment of prostate cancer (PCa) remains a major challenge due to chemoresistance to drugs including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Ethanol and ethanol extracts are known apoptosis inducers. However, cytotoxic effects of ethanol on PCa cells are unclear.Methods:In this study we utilized PC3 and LNCaP cell culture models. We used immunohistochemical analysis, western blot analysis, reactive oxygen species (ROS) measurement, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) Cell Proliferation Assay, Annexin-V staining and flow cytometry for quantification of apoptosis. In vitro soft agar colony formation and Boyden chamber invasion assays were used. Tumorigenicity was measured in a xenotransplantation mouse model.Results:Here, we demonstrate that ethanol enhances the apoptosis-inducing potential of TRAIL in androgen-resistant PC3 cells and sensitizes TRAIL-resistant, androgen sensitive LNCaP cells to apoptosis through caspase activation, and a complete cleavage of poly (ADP)-ribose polymerase, which was in association with increased production of ROS. The cytotoxicity of ethanol was suppressed by an antioxidant N-acetyl cystein pretreatment. Furthermore, ethanol in combination with TRAIL increased the expression of cyclin-dependent kinase inhibitor p21 and decreased the levels of Bcl-2 and phosphorylated-AKT. These molecular changes were accompanied by decreased proliferation, anchorage-independent growth and invasive potential of PC3 and LNCaP cells. In vivo studies using a xenotransplantation mouse model with PC3 cells demonstrated significantly increased apoptosis in tumors treated with ethanol and TRAIL in combination.Conclusions:Taken together, use of ethanol in combination with TRAIL may be an effective strategy to augment sensitivity to TRAIL-induced apoptosis in PCa cells.Prostate Cancer and Prostatic Disease advance online publication, 18 September 2012; doi:10.1038/pcan.2012.37.
Authors:
M K Plante; W T Arscott; J B Folsom; S W Tighe; R J Dempsey; U V Wesley
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-9-18
Journal Detail:
Title:  Prostate cancer and prostatic diseases     Volume:  -     ISSN:  1476-5608     ISO Abbreviation:  Prostate Cancer Prostatic Dis.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-9-18     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9815755     Medline TA:  Prostate Cancer Prostatic Dis     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1] Department of Surgery and Urology, University of Vermont, Burlington, VT, USA [2] Vermont Cancer Center, University of Vermont, Burlington, VT, USA.
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