Two New Adenosine Derivatives and their Antiproliferative Properties: An <i>In Vitro</i> Evaluation

Author(s):

Francisco Valdés, Bárbara Arévalo, Margarita Gutiérrez, Verónica García-Castillo, Rebeca Salgado-García, Carlos Pérez-Plasencia*, Claudio Valenzuela, Ángel Cayo, Alexandra Olate-Briones and Nelson Brown *   Pages 1414 - 1425 ( 12 )

Abstract:

Background: Adenosine is a natural nucleoside present in a variety of organs and tissues, where it acts as a modulator of diverse physiological and pathophysiological processes. These actions are mediated by at least four G protein-coupled receptors, which are widely and differentially expressed in tissues. Interestingly, high concentrations of adenosine have been reported in a variety of tumors. In this context, the final output of adenosine in tumorigenesis will likely depend on the constellation of adenosine receptors expressed by tumor and stromal cells. Notably, activation of the A3 receptor can reduce the proliferative capacity of various cancer cells. <P> Objective: This study aimed to describe the anti-proliferative effects of two previously synthesized adenosine derivatives with A3 agonist action (compounds 2b and 2f) through in vitro assays. <P> Methods: We used gastric and breast cancer cell lines expressing the A3 receptor as in vitro models and theoretical experiments for molecular dynamics and determination of ADME properties. <P> Results: The antiproliferative effects of adenosine derivatives (after determining IC50 values) were comparable or even higher than those described for IB-MECA, a commercially available A3 agonist. Among possible mechanisms involved, apoptosis was found to be induced in MCF-7 cells but not in AGS or MDA-MB-231 cells. Surprisingly, we were unable to observe cellular senescence induction upon treatment with compounds 2b and 2f in any of the cell lines studied, although we cannot rule out other forms of cell cycles exit at this point. <P> Conclusion: Both adenosine derivatives showed antiproliferative effects on gastric and breast cancer cell lines, and were able to induce apoptosis, at least in the MCF-7 cell line. Further studies will be necessary to unveil receptor specificity and mechanisms accounting for the antiproliferative properties of these novel semi-synthetic compounds.

Keywords:

Adenosine, A3 receptor, adenosine derivatives, apoptosis, molecular dynamics, ADME profiles, cancer cells.

Affiliation:

Organic Synthesis Laboratory and Biological Activity (LSO-Act-Bio), PhD Sciences Mention Investigation and Development of Bioactive Products, Institute of Chemistry of Natural Resources, University of Talca, Centro de Estudios en Alimentos Procesados- CEAP, Conicyt, Programa Regional R19A10001, Gore Maule, Talca, Chile; 3Institute of Chemistry of Natural Resources, University of Talca, Institute of Chemistry of Natural Resources, University of Talca, FES-Iztacala, UBIMED, National Autonomous University of Mexico, UNAM, Tlalnepantla, Genomics Lab, National Cancer Institute of Mexico, FES-Iztacala, UBIMED, National Autonomous University of Mexico, UNAM, Tlalnepantla, Medical School, University of Talca, Medical School, University of Talca, Medical School, University of Talca, Medical School, University of Talca

Graphical Abstract:

Read Full-Text article