Alterations in Red Blood Cell Functionality Induced by an Indole Scaffold Containing a Y-Iminodiketo Moiety: Potential Antiproliferative Conditions

We have recently proposed a new erythrocyte-based model of study to predict the antiproliferative effects of selected heterocyclic
scaffolds. Starting from the metabolic similarity between erythrocytes and cancer cells, we have demonstrated how the metabolic
derangement induced by an indolone-based compound (DPIT) could be related to its antiproliferative effects. In order to prove
the validity of our biochemical approach, in the present study the effects on erythrocyte functionality of its chemical precursor
(PID), whose synthesis we reported, were investigated. The influence of the tested compound on band 3 protein (B3), oxidative
state, ATP efflux, caspase 3, metabolism, intracellular pH, and Ca2+ homeostasis has been evaluated. PID crosses the membrane
localizing into the cytosol, increases anion exchange, induces direct caspase activation, shifts the erythrocytes towards an oxidative
state, and releases less ATP than in normal conditions. Analysis of phosphatidylserine externalization shows that PID slightly
induces apoptosis. Our findings indicate that, due to its unique features, erythrocyte responses to exogenous molecular stimuli can
be fruitfully correlated at structurally more complex cells, such as cancer cells. Overall, our work indicates that erythrocyte is a
powerful study tool to elucidate the biochemical/biological effects of selected heterocycles opening considerable perspectives in
the field of drug discovery.