title: Cellular trafficking, accumulation and DNA platination of a series of cisplatin-based dicarboxylato Pt(IV) prodrugs.
abstract: A series of Pt(IV) anticancer prodrug candidates, having the equatorial arrangement of cisplatin and bearing two aliphatic carboxylato axial ligands, has been investigated to prove the relationship between lipophilicity, cellular accumulation, DNA platination and antiproliferative activity on the cisplatin-sensitive A2780 ovarian cancer cell line. Unlike cisplatin, no facilitated influx/efflux mechanism appears to operate in the case of the Pt(IV) complexes under investigation, thus indicating that they enter by passive diffusion. While Pt(IV) complexes having lipophilicity comparable to that of cisplatin (negative values of log Po/w) exhibit a cellular accumulation similar to that of cisplatin, the most lipophilic complexes of the series show much higher cellular accumulation (stemming from enhanced passive diffusion), accompanied by greater DNA platination and cell growth inhibition. Even if the Pt(IV) complexes are removed from the culture medium in the recovery process, the level of DNA platination remains very high and persistent in time, indicating efficient storing of the complexes and poor detoxification efficiency.
authors.affiliation: Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale T. 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 T. 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 T. 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 T. Michel 11, 15121 Alessandria, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bonarrigo
authors.affiliation: Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale T. Michel 11, 15121 Alessandria, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Alessio
authors.affiliation: Dipartimento di Chimica, Università di Bari "Aldo Moro", Via E. Orabona, 4, 70125 Bari, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Arnesano
authors.affiliation: Dipartimento di Chimica, Università di Bari "Aldo Moro", Via E. Orabona, 4, 70125 Bari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Galliani
authors.affiliation: Dipartimento di Chimica, Università di Bari "Aldo Moro", Via E. Orabona, 4, 70125 Bari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile
authors.affiliation: Dipartimento di Scienze e Innovazione Tecnologica, Università del Piemonte Orientale, Viale T. Michel 11, 15121 Alessandria, Italy. Electronic address: domenico.osella@uniupo.it.
authors.forename: Domenico
authors.initials: D
authors.lastname: Osella
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000737:chemistry; D027682:Cation Transport Proteins / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D004058:Diffusion; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009842:Oligopeptides / Q000737:chemistry; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010446:Peptide Fragments; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C000610396:ATP7A protein, human (2-79); D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D018736:DNA Adducts; C000610395:Mets7 peptide; D009842:Oligopeptides; D009944:Organoplatinum Compounds; D010446:Peptide Fragments; D011355:Prodrugs; C490079:SLC31A1 protein, human; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; D005978:Glutathione; D001205:Ascorbic Acid; D002945:Cisplatin
keywords: Cell growth inhibition; Cellular accumulation; DNA platination; Lipophilicity; Pt(IV) complexes