Malignant pleural mesothelioma (MPM) is a rare and aggressive asbestos-related cancer. It is intrinsically resistant to both chemotherapy and radiation treatment. MPM is chemoresistant thanks to glutathione (GSH), which deactivates Pt-based drugs. Currently, all poly-chemotherapeutic protocols for treating MPM include cisplatin or carboplatin. Ethacrynic acid (EA) inhibits the enzyme that catalyses the conjugation between GSH and Pt-based drugs. A Pt^IV derivative containing a cisplatin
equatorial base and two axial EA anions, namely cis,cis,trans-diamminodichloridobis(ethacrynato)platinum(IV), 1, also known as ethacraplatin has  been synthesized. The idea is that a bifunctional molecule composed of a Pt complex and EA
could combine the cytotoxic activity of the metal drug with lower chemoresistance.

Domenico Osella and co-workers, University of Piemonte Orientale Amedeo Avogadro, Italy, synthesized and charaterized  the bifunctional EA–Pt^II complex 2 (cis-diamminobis(ethacrynato) platinum(II)). It contains two EA moieties as leaving groups. The complex was tested on four MPM cell lines. The resulting antiproliferative activity was compared with that elicited by the analogue Pt^IV complex ethacraplatin, 1, 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.

• Evaluation of Platinum–Ethacrynic Acid Conjugates in the Treatment of Mesothelioma
  I. Zanellato, I. Bonarrigo, M. Sardi, M. Alessio, E. Gabano, M. Ravera, D. Osella,
  ChemMedChem 2011.
  DOI: 10.1002/cmdc.201100426