I. Bellezza, A. Tucci, A. Minelli
Sep 30, 2008
Anti-cancer agents in medicinal chemistry
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.