Cytostatic Effect of the Nucleoside Analogue 2-Chloroadenosine on Human Prostate Cancer Cell Line

Ilaria      Bellezza; Massimiliano      Agostini; Lavinia      Liguori; Alba      Minelli

Abstract

2-Chloroadenosine is an adenosine analog capable of inducing apoptosis in several cell lines by acting either via adenosine receptors or via uptake that is followed by metabolic transformations leading to nucleotide analogs. DNAdirected nucleotide analogs are antimetabolites effective in the treatment of a variety of malignancies. Triphosphate nucleoside analogs show specificity for cells in S-phase, inhibit DNA synthesis, and kill the cells by mechanisms still largely unknown. It is likely that cells perceive sublethal incorporation of analogues into DNA and react by arresting further DNA synthesis and cell cycle progression. After removal of the drug, cells resume progression and proliferation, escaping nucleoside analog toxicity. The induction of cytostasis and subsequent recovery may mimic a mechanism of resistance to nucleoside analogs that represents a major problem in cancer chemotherapy. 2-Chloroadenosine, acting as metabolic precursor of an S-phase specific nucleoside analogue in human prostate cancer PC3 cells, inhibited DNA synthesis so that the cell population accumulated in the S-phase. After release from the S-phase, proliferation continued and cells exhibited a lag before resuming proliferation at a rate comparable with controls. The combination of 2- chloroadenosine with staurosporine, a cell cycle checkpoint dysregulator, enhances the killing potential of the antineoplastic agent and diminishes the effective antineoplastic dose. Hence, the nucleoside analog might be proposed as an essential component of an effective drug combination for advanced prostate cancer. This study, as well as providing the reader with up-to date literature on 2-chloroadenosine, presents new data hinting at the possible therapeutic use of this analog.

Keywords: 2-chloroadenosine, cell cycle, dna synthesis, staurosporine, antineoplastic agents sensitization

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