Evaluation of Platinum-Ethacrynic Acid Conjugates in the Treatment of Mesothelioma

Ilaria Zanellato, Ilaria Bonarrigo, Manuele Sardi, Manuela Alessio, Elisabetta Gabano, Mauro Ravera, Domenico Osella

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

Abstract

Malignant pleural mesothelioma (MPM) cells are characterized by chemoresistance associated with glutathione (GSH) metabolism. Ethacrynic acid (EA) is able to inhibit the detoxifying enzyme glutathione-S-transferase (GST), which catalyzes the conjugation between GSH and Pt-based drugs. With the aim of obtaining active bifunctional drugs, a Pt II complex containing two EA moieties as leaving groups, namely cis-diamminobis(ethacrynato)platinum(II), was synthesized, characterized, and tested on four MPM cell lines. The resulting antiproliferative activity was compared with that elicited by the analogue Pt IV complex, cis,cis,trans-diamminodichloridobis(ethacrynato)platinum(IV) (ethacraplatin) and by the co-administration of free EA and cisplatin. The Pt II and Pt IV bifunctional complexes showed poorer performance than the reference drug cisplatin alone or in combination with EA. After treatment, cellular GST activity remained consistently unchanged, while the GSH level increased. Fighting fire with fire: Malignant pleural mesothelioma cells are chemoresistant thanks to glutathione (GSH), which deactivates Pt-based drugs. Ethacrynic acid (EA) inhibits the enzyme that catalyzes the conjugation between GSH and Pt drugs. We therefore synthesized and characterized a bifunctional drug-a Pt II complex containing EA-and tested it on four mesothelioma cell lines in comparison with its analogue Pt IV complex, ethacraplatin.

Lingua originaleInglese
pagine (da-a)2287-2293
Numero di pagine7
RivistaChemMedChem
Volume6
Numero di pubblicazione12
DOI
Stato di pubblicazionePubblicato - 9 dic 2011

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