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

被引：32

作者：

Gabano, Elisabetta ^{[1
]}

Ravera, Mauro ^{[1
]}

Trivero, Francesca ^{[1
]}

Tinello, Stefano ^{[1
]}

Gallina, Andrea ^{[1
]}

Zanellato, Ilaria ^{[1
]}

Gariboldi, Marzia B. ^{[2
]}

Monti, Elena ^{[2
]}

Osella, Domenico ^{[1
]}

机构：

[1] Univ Piemonte Orientale, Dipartimento Sci & Innovaz Tecnol, Viale Michel 11, I-15121 Alessandria, Italy

[2] Univ Insubria, Dipartimento Biotecnol & Sci Vita, Via Manara 7, I-21052 Busto Arsizio, VA, Italy

来源：

DALTON TRANSACTIONS | 2018年 / 47卷 / 25期

关键词：

ALPHA PPAR-ALPHA; HUMAN OVARIAN-CANCER; PLATINUM(IV) COMPLEXES; PT(II) COMPLEXES; NMR-SPECTROSCOPY; ANTIPROLIFERATIVE ACTIVITY; INDUCED RESISTANCE; ANTITUMOR PRODRUG; DRUG-COMBINATION; CYTOTOXIC AGENTS;

D O I：

10.1039/c7dt04614f

中图分类号：

O61 [无机化学];

学科分类号：

070301 ; 081704 ;

摘要：

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.

引用

页码：8268 / 8282

页数：15

共 83 条

[1] Hypoxia-Induced Cytotoxic Drug Resistance in Osteosarcoma Is Independent of HIF-1Alpha [J].