Cladribine, i.e.2-deoxy-Chloroadenosine is currently in use as chemotherapeutic agent in chronic lymphoid
malignancies and pediatric
acute myelogenous leukemia whereas the structurally related counterpart,
2-Chloroadenosine, has been less studied. Nevertheless,
2-Chloroadenosine has been shown to be 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 analogues, i.e.
antimetabolites effective in the treatment of a variety of
malignancies.
Triphosphate nucleoside analogues show specificity for cell in S-phase, inhibit
DNA synthesis and kill the cells by mechanisms still largely unknown.
2-Chloroadenosine, at low micromolar concentration, acts as a metabolic precursor of an S-phase specific
nucleoside analogue in human
prostate cancer PC3 cells and inhibits
DNA synthesis thereby leading to accumulation of cells in the S-phase. However, although responsible for the acquisition of resistance, the
adenosine derivative is capable of sensitising the cells to the action of other
antineoplastic agents and the ability of
nucleoside analogues to trigger cell cycle arrest can be exploited to maximize cytotoxicity in combination with cell cycle checkpoint disregulators.
2-Chloroadenosine, in combination with
Docetaxel, known to improve the survival of
hormone-refractory
prostate cancer patients, further decreases in vitro PC3 cell proliferation and invasiveness. Moreover,
2-Chloroadenosine is capable of modulating PAR-1 and
IL-23 gene expression suggesting a modulation of
cancer metastasis and immune system activity. The present review summarizes research performed in our laboratory to propose a novel role for
2-Chloroadenosine as an
anticancer agent.