title: Alterations in Red Blood Cell Functionality Induced by an Indole Scaffold Containing a Y-Iminodiketo Moiety: Potential Antiproliferative Conditions.
abstract: 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 Ca(2+) 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.
authors.affiliation: Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, Università di Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Scala
authors.affiliation: Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, Università di Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Ficarra
authors.affiliation: Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, Università di Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Russo
authors.affiliation: Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, Università di Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy.
authors.forename: Davide
authors.identifier: 0000-0002-1463-4069
authors.initials: D
authors.lastname: Barreca
authors.affiliation: Virologia e Microbiologia AOOR Papardo-Piemonte, Viale F. Stagno d'Alcontres, 98166 Messina, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Giunta
authors.affiliation: Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, Università di Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Galtieri
authors.affiliation: Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, Università di Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy.
authors.forename: Giovanni
authors.identifier: 0000-0003-1687-192X
authors.initials: G
authors.lastname: Grassi
authors.affiliation: Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, Università di Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Tellone
mesh_terms: D000255:Adenosine Triphosphate / Q000097:blood; D001457:Anion Exchange Protein 1, Erythrocyte / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000097:blood; D020169:Caspases / Q000097:blood; D004789:Enzyme Activation / Q000187:drug effects; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000494:pharmacology*
chemical_list: C000595203:2,2'-dimethyl-6,6'-diphenyl-6,6',7,7'-tetrahydro-1H,1'H-2,3'-biindole-3,4,4'(2H,5H,5'H)-trione; D001457:Anion Exchange Protein 1, Erythrocyte; D007211:Indoles; D000255:Adenosine Triphosphate; D020169:Caspases; D002118:Calcium