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Evaluation of Platinum–Ethacrynic Acid Conjugates in the Treatment of Mesothelioma
Author(s) -
Zanellato Ilaria,
Bonarrigo Ilaria,
Sardi Manuele,
Alessio Manuela,
Gabano Elisabetta,
Ravera Mauro,
Osella Domenico
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100426
Subject(s) - cisplatin , glutathione , bifunctional , chemistry , platinum , conjugate , mesothelioma , pharmacology , enzyme , biochemistry , stereochemistry , chemotherapy , medicine , catalysis , pathology , mathematical analysis , mathematics
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.