Farmacologia Molecular dels Transportadors de Nucleòsids en Teràpia del Càncer: Nucleòsids Naturals No Canònics i Ruxolitinib

Abstract

Nucleoside transporters are essential for nucleotide homeostasis as well as for nucleoside-derived drugs bioavailability. Non-canonical natural nucleosides or “epigenetic nucleosides” are endogenously produced and possess pharmacological properties. Their pharmacological action depends on cytidine deaminase activity, which is a typical mechanism of chemoresistance induction for nucleoside-derived drugs. Thus, epigenetic nucleosides show a potential singular status in terms of cancer therapy approach. However, the interplay between these nucleosides and nucleoside transporters which might facilitate their bioavalability remains unknown. In order to unveil that question both interaction and translocation aspects of epigenetic nucleosides towards nucleoside transporters are addressed within this work.

In addition to epigenetic nucleosides, the possible interaction of ruxolitinib with nucleoside transporters is also studied in this work. Ruxolitinib is a Janus kinase inhibitor used for the treatment of negative Philadelphia- chromosome chronic myeloproliferative neoplasms. Since it is well known and perfectly established that several kinase inhibitors are recognized by nucleoside transporters, the same question has been raised for ruxolitinib. Additionally, the molecular structure of ruxolitinib contains a heterocycle which is highly similar to hypoxanthine, a key structural determinant for purine nucleoside recognition by nucleoside transporters. That particularity together with the fact that the main cell target of ruxolitinib are hematopoietic precursors which lack de novo nucleotide synthesis and completely depend on nucleoside salvage pathway make ruxolitinib a good candidate in terms of its interaction with nucleoside transporters.

As a result of this work, it is shown that epigenetic nucleosides are recognized by nucleoside transporters being even translocated by them in some cases. To that extent, two associations stand out over the rest: 5hmdC with hCNT1 and 5fdC with hENT1. The critical factor which determines molecular recognition turns out to be the chemical environment provided by the functional group at position 5 of the pyrimidine ring of the nucleoside. Unexpectedly, 5fdC turns out to be recognized and even transported by the purine-preferring transporter hCNT2. As to ruxolitinib, its interaction with hENT1 is elucidated. Due to this interaction, ruxolitinib has the capacity to modulate the pharmacological activity of nucleoside-derived drugs such as gemcitabine by inhibiting hENT1 activity.