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 alpha (PPAR alpha) that, in turn, decreases the level of Hypoxia-Inducible Factor-1 alpha 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.

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

Gariboldi MB;Monti E;
2018-01-01

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 alpha (PPAR alpha) that, in turn, decreases the level of Hypoxia-Inducible Factor-1 alpha 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.
2018
http://pubs.rsc.org/en/journals/journal/dt
Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cisplatin; Clofibric Acid; Dose-Response Relationship, Drug; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inhibitory Concentration 50; Molecular Structure; Organoplatinum Compounds; Oxidative Stress; PPAR alpha; Prodrugs; Inorganic Chemistry
Gabano, E; Ravera, M; Trivero, F; Tinello, S; Gallina, A; Zanellato, I; Gariboldi, Mb; Monti, E; Osella, D.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11383/2074615
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