The cisplatin-based Pt(iv)-diclorofibrato multi-action anticancer prodrug exhibits excellent performances also under hypoxic conditions

Elisabetta Gabano, Mauro Ravera, Francesca Trivero, Stefano Tinello, Andrea Gallina, Ilaria Zanellato, Marzia B. Gariboldi, Elena Monti, Domenico Osella

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

Abstract

Multi-action cisplatin-based mono- (1) and di-clofibric acid (2) Pt(iv) "combo" derivatives were synthesized via both traditional and microwave assisted procedures. The two complexes offered very good performances (IC50 values in a nanomolar range) on a panel of human tumor cell lines, including the highly chemoresistant malignant pleural mesothelioma ones. Moreover, both 1 and 2 bypass the cisplatin resistance. Indeed, cisplatin and clofibric acid, the metabolites of the Pt(iv) → Pt(ii) intracellular reduction, proved to act synergistically. The adjuvant action of clofibric acid relies on the activation of peroxisome proliferator-activated receptor α (PPARα) that, in turn, decreases the level of Hypoxia-Inducible Factor-1α. Both compounds induced extensive apoptosis in tumor cells, also via oxidative stress. Finally, 2 exhibited excellent performances also under the hypoxic conditions typical of solid tumors, where cisplatin is less effective.

Lingua originaleInglese
pagine (da-a)8268-8282
Numero di pagine15
RivistaDalton Transactions
Volume47
Numero di pubblicazione25
DOI
Stato di pubblicazionePubblicato - 2018

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