Document Detail

Arsenic trioxide suppresses thymidylate synthase in 5-FU-resistant colorectal cancer cell line HT29 In Vitro re-sensitizing cells to 5-FU.
MedLine Citation:
PMID:  20530422     Owner:  NLM     Status:  MEDLINE    
Identification of new agents with antitumor activity in chemoresistant tumors is urgently needed for the treatment of colorectal cancer. Arsenic trioxide (As(2)O(3)), a Food and Drug Administration (FDA) approved drug is successfully being used to treat acute promyelocytic leukemia (APL). Several clinical trials also suggest its ineffectiveness on solid tumors. We proposed that arsenic trioxide may be used as chemosensitizer, especially to 5-fluorouracil (5-FU). The effect of arsenic trioxide on cell proliferation of 5-FU-sensitive and -resistant HT29 colorectal cancer cells in vitro was tested by trypan blue dye exclusion assay, 2, 3-bis(2-methoxy-4-nitro-5-sulfophenyl)-S-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide (XTT) cell proliferation assay and cell cycle analysis using flow cytometry. Gene expression was analyzed using real-time polymerase chain reaction (PCR) and Western blot methods. There was a dose-dependent increase in cell detachment and proliferation in HT29 and HT29FU cells. As a single agent, arsenic trioxide also down-regulated thymidylate synthase (TS) expression without affecting the expression of some other genes analyzed in the above cell lines. Combination of arsenic trioxide and 5-FU increased cytotoxicity. In vitro data show that as a single agent, arsenic trioxide down-regulated TS expression in HT29 cells. Addition of 5-FU to these sensitized cells increased cytotoxicity. These findings open up a possibility to use arsenic trioxide as a chemosensitizer in combination therapy.
Pochi Ramalingam Subbarayan; Kelvin Lee; Bach Ardalan
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Anticancer research     Volume:  30     ISSN:  1791-7530     ISO Abbreviation:  Anticancer Res.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-06-09     Completed Date:  2010-06-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8102988     Medline TA:  Anticancer Res     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  1157-62     Citation Subset:  IM    
Department of Medicine, Division of Hematology and Oncology, University of Miami School of Medicine, Miami, FL 33136, USA.
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MeSH Terms
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Arsenicals / administration & dosage,  pharmacology*
Blotting, Western
Colorectal Neoplasms / drug therapy*,  enzymology*
Drug Resistance, Neoplasm
Drug Synergism
Fluorouracil / administration & dosage,  pharmacology*
Gene Expression / drug effects
HT29 Cells
Oxides / administration & dosage,  pharmacology*
RNA, Messenger / biosynthesis,  genetics
Reverse Transcriptase Polymerase Chain Reaction
Thymidylate Synthase / antagonists & inhibitors*,  biosynthesis,  genetics
Tumor Suppressor Protein p53 / biosynthesis,  genetics
Reg. No./Substance:
0/Arsenicals; 0/Oxides; 0/RNA, Messenger; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 1327-53-3/arsenic trioxide; 51-21-8/Fluorouracil; EC Synthase

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