Allosteric inhibitors targeting 5’-nucleotidases to restore the antitumor therapy efficacy
In humans, eight 5'-nucleotidases catalyze the hydrolysis of nucleoside 5'-monophosphates into their respective nucleosides in order to regulate the intracellular / extracellular nucleotide pools. Two main enzymes, cytosolic 5’-nucleotidase II (cN-II) and ecto-5’-nucleotidase (CD73) have been identified as main therapeutic targets in cancer. Indeed, cN-II is involved in resistance to hematological cancer treatments while CD73-generated adenosine was shown to be a potent suppressor of the anticancer immune response in breast, colorectal, bladder, pancreas and ovarian cancers. CD73 is overexpressed in cancerous and endothelial cells and promotes tumor growth, cell invasion and tumor metastasis through the action of adenosine binding to P1 receptors (immune cells).
For instance, the treatment of acute myeloid leukemia (AML) with cytarabine led to a worse patient outcome when cN-II was over-expressed . Moreover, an enzyme hyperactivity was recently correlated with resistance to several chemotherapies in relapsed patients [2-3]. On the other hand, the inhibition of CD73 activity either by siRNA, substrate analogs or mAb led to tumor regression and restore the immune response through ATP signaling.
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