Document Detail


Differential activation of cell death and autophagy results in an increased cytotoxic potential for trifluorothymidine compared to 5-fluorouracil in colon cancer cells.
MedLine Citation:
PMID:  19816940     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Trifluorothymidine (TFT) is part of the oral drug formulation TAS-102. Both 5-fluorouracil (5-FU) and TFT can inhibit thymidylate synthase and be incorporated into DNA. TFT shows only moderate cross-resistance to 5-FU. Therefore, we examined whether mechanistic differences in cell death could underlie their different modes of action in colorectal cancer cell lines (WiDR, Lovo92 and Colo320). Drug cytotoxicity was determined by SRB- and clonogenic assays, cell death by flow cytometry (PI and annexin V), caspase cleavage by Western blotting and activity assays and in vivo activity in the hollow fiber assay. The IC(50) values of TFT were 1-6 fold lower than for 5-FU, and clonogenic survival was less than 0.9% at 3 muM TFT, while 2-20% of the cells still survived after 20 muM 5-FU. In general, TFT was a more potent inducer of apoptosis than 5-FU, although the contribution of caspases varied between the used cell lines and necrosis-like cell death was detected. Accordingly, both drugs induced caspase (Z-VAD) independent cell death and lysosomal cathepsin B was involved. Activation of autophagy recovery mechanisms was only triggered by 5-FU, but not by TFT as determined by LC3B expression and cleavage. Inhibition of autophagy by 3-MA in 5-FU exposed cells reduced cell survival. Also, in vivo TFT (as TAS-102) caused more cell death than a 5-FU formulation. We conclude that TFT and 5-FU induce cell death via both caspase-dependent and independent mechanisms. The TFT was more potent than 5-FU, because it induces higher levels of cell death and does not elicit an autophagic survival response in the cancer cell lines. This provides a strong molecular basis for further application of TFT in cancer therapy.
Authors:
Irene V Bijnsdorp; Godefridus J Peters; Olaf H Temmink; Masakazu Fukushima; Frank A Kruyt
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  126     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-03-29     Completed Date:  2010-04-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2457-68     Citation Subset:  IM    
Affiliation:
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
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MeSH Terms
Descriptor/Qualifier:
Antimetabolites, Antineoplastic / pharmacology*
Apoptosis / drug effects*
Autophagy / drug effects*
Blotting, Western
Caspases / metabolism
Cathepsin B / metabolism
Cell Line, Tumor
Colonic Neoplasms / drug therapy*,  enzymology
Flow Cytometry
Fluorescent Antibody Technique
Fluorouracil / pharmacology*
Humans
Necrosis
Trifluridine / pharmacology*
Tumor Stem Cell Assay
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 51-21-8/Fluorouracil; 70-00-8/Trifluridine; EC 3.4.22.-/Caspases; EC 3.4.22.1/Cathepsin B

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