TY - JOUR
T1 - Evaluation of Platinum-Ethacrynic Acid Conjugates in the Treatment of Mesothelioma
AU - Zanellato, Ilaria
AU - Bonarrigo, Ilaria
AU - Sardi, Manuele
AU - Alessio, Manuela
AU - Gabano, Elisabetta
AU - Ravera, Mauro
AU - Osella, Domenico
PY - 2011/12/9
Y1 - 2011/12/9
N2 - 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.
AB - 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.
KW - Antitumor agents
KW - Cancer
KW - Ethacrynic acid
KW - Glutathione-S-transferase
KW - Malignant mesothelioma
KW - Platinum
UR - http://www.scopus.com/inward/record.url?scp=82955161519&partnerID=8YFLogxK
U2 - 10.1002/cmdc.201100426
DO - 10.1002/cmdc.201100426
M3 - Article
SN - 1860-7179
VL - 6
SP - 2287
EP - 2293
JO - ChemMedChem
JF - ChemMedChem
IS - 12
ER -