Anticancer properties and mechanism of action of the fungal nucleoside clitocine and its derivatives

Clitocine (CLT) is an atypical nitro-containing pyrimidine nucleoside bearing a ribofuranosyl moiety attached to the exocyclic 4-amino position. It has been isolated first from the fungus Clitocybe inversa and then from fruiting bodies of Leucopaxillus giganteus. Two intramolecular hydrogen-bonds between adjacent amino and nitro groups on the pyrimidine unit confer a planar structure to the pseudo-tricyclic core of the molecule, thus facilitating stacking interactions with aromatic amino acid or the nucleobases. Over the past thirty years, a variety of CLT analogues have been synthesized, including amino derivatives acting as potent inhibitors of adenosine kinase, and a variety of other molecules all described here. The antitumor action of the mushroom extracts and purified CLT has been evidenced in murine models. The capacity of CLT to reduce tumor cell proliferation, to trigger apoptosis and to inhibit tumor growth in mice have been associated with a drug-induced modulation of the NF-kappa B and Akt pathways, notably with a down-regulation and proteasome-dependent degradation of anti-apoptotic protein Mcl-1. The potential targeting of an upstream protein effector, possibly the kinase Akt, is discussed. Moreover, CLT can promote translational readthrough of stop codons. This emerging mechanism reinforces further the interest of the natural product to address different types of cancers and nonsense mutation-related genetic disorders. Altogether, the review provides an overview of the history of CLT, from its chemical discovery in fungi to the identification of its anticancer activities and different mechanisms of action. Research prospects are proposed to better delineate the mode of action of this original natural product and to promote mycomedicine.