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Full Paper
Evaluation of Platinum–Ethacrynic Acid Conjugates in the Treatment of Mesothelioma
Article first published online: 24 OCT 2011
DOI: 10.1002/cmdc.201100426
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Additional Information
How to Cite
Zanellato, I., Bonarrigo, I., Sardi, M., Alessio, M., Gabano, E., Ravera, M. and Osella, D. (2011), Evaluation of Platinum–Ethacrynic Acid Conjugates in the Treatment of Mesothelioma. ChemMedChem, 6: 2287–2293. doi: 10.1002/cmdc.201100426
Publication History
- Issue published online: 2 DEC 2011
- Article first published online: 24 OCT 2011
- Manuscript Revised: 11 OCT 2011
- Manuscript Received: 8 SEP 2011
Funded by
- Provincia di Alessandria
- CRA Foundation
Keywords:
- antitumor agents;
- cancer;
- ethacrynic acid;
- glutathione-S-transferase;
- malignant mesothelioma;
- platinum
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 PtII 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 PtIV complex, cis,cis,trans-diamminodichloridobis(ethacrynato)platinum(IV) (ethacraplatin) and by the co-administration of free EA and cisplatin. The PtII and PtIV 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.