title: May glutamine addiction drive the delivery of antitumor cisplatin-based Pt(IV) prodrugs?
abstract: A small series of Pt(IV) prodrugs containing Gln-like (Gln=glutamine) axial ligands has been designed with the aim to take advantage of the increased demand of Gln showed by some cancer cells (glutamine addiction). In complex 4 the Gln, linked through the α-carboxylic group is recognized by the Gln transporters, in particular by the solute carrier transporter SLC1A5. All compounds showed cellular accumulation, as well as antiproliferative activity, related to their lipophilicity, as already demonstrated for the majority of Pt(IV) prodrugs, that enter cells mainly by passive diffusion. On the contrary, when the Gln concentration in cell medium is near or lower to the physiological value, complex 4 acts as a Trojan horse: it enters SLC1A5-overexpressing cells, where, upon reduction, it releases the active metabolite cisplatin and the Gln-containing ligand, thus preventing any possible extrusion by the L-type amino acid transporter LAT1. This selective mechanism could decrease off-target accumulation of 4 and, consequently, Pt-associated side-effects.
authors.affiliation: Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale Michel 11, 15121 Alessandria, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Ravera
authors.affiliation: Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale Michel 11, 15121 Alessandria, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gabano
authors.affiliation: Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale Michel 11, 15121 Alessandria, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Tinello
authors.affiliation: Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale Michel 11, 15121 Alessandria, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Zanellato
authors.affiliation: Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale Michel 11, 15121 Alessandria, Italy. Electronic address: domenico.osella@uniupo.it.
authors.forename: Domenico
authors.initials: D
authors.lastname: Osella
mesh_terms: D000072283:A549 Cells; D026962:Amino Acid Transport System ASC / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005973:Glutamine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D026962:Amino Acid Transport System ASC; D000970:Antineoplastic Agents; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; D011355:Prodrugs; C420506:SLC1A5 protein, human; D005973:Glutamine; D002945:Cisplatin
keywords: Anticancer prodrugs; Cancer metabolism; Drug targeting and delivery; Glutamine metabolism; Pt(IV) complexes