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Mechanism of 2‐chloroadenosine toxicity to PC3 cell line
Author(s) -
Minelli Alba,
Bellezza Ilaria,
Agostini Massimiliano,
Bracarda Sergio,
Culig Zoran
Publication year - 2006
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20458
Subject(s) - ribonucleotide reductase , cell cycle , cell growth , biology , dna synthesis , biochemistry , enzyme , nucleotide salvage , prostate cancer , apoptosis , cancer research , dna , microbiology and biotechnology , chemistry , cancer , nucleotide , protein subunit , genetics , gene
BACKGROUND 2‐CADO inhibits the growth of several types of cells and causes apoptosis by a mechanism which involves adenosine receptors or cellular uptake or both. METHODS Androgen‐independent (PC3) prostate cancer cells were used in the study and proliferation, cell‐cycle progression, and apoptosis analyzed. Deoxy‐and ribonucleoside triphosphate pools were determined by HPLC. The molecular mechanism was examined by assessing the involvement of DNA synthesizing enzymes in the cellular response. RESULTS 2‐CADO treatment dramatically reduced the number of prostate cancer cells and permanently stopped cell‐cycle progression in the S‐phase. The role of 2‐CADO in prostate cancer cells is uptake‐mediated and followed by sequential phosphorylations to 2‐Cl‐ATP that irreversibly inhibits several key‐enzymes for DNA biosynthesis. CONCLUSIONS Arrest of DNA synthesis responsible for toxicity of 2‐CADO to PC3 cells is due to the lack of substrates for DNA polymerization caused by irreversible inhibition of purine/pyrimidine ribo‐and 2‐deoxyribonucleotides salvage enzymes. Prostate 66: 1425–1436, 2006. © 2006 Wiley‐Liss, Inc.