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

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.