The search for more effective and selective drugs to overcome cancer multidrug resistance is urgent. As such, a new series of ruthenium-cyclopentadienyl ("RuCp") compounds with the general formula [Ru(eta(5)-C5H4R)(4,4 '-R '-2,2 '-bipy)(PPh3)] were prepared and fully characterized. All compounds were evaluated toward non-small cell lung cancer cells with different degrees of cisplatin sensitivity (A549, NCI-H2228, Calu-3, and NCI-H1975), showing better cytotoxicity than the first-line chemotherapeutic drug cisplatin. Compounds 2 and 3 (R ' = -OCH3; R = CHO (2) or CH2OH (3)) further inhibited the activity of P-gp and MRP1 efflux pumps by impairing their catalytic activity. Molecular docking calculations identified the R-site P-gp pocket as the preferred one, which was further validated using site-directed mutagenesis experiments in P-gp. Altogether, our results unveil the first direct evidence of the interaction between P-gp and "RuCp" compounds in the modulation of P-gp activity and establish them as valuable candidates to circumvent cancer MDR.

Fighting Multidrug Resistance with Ruthenium-Cyclopentadienyl Compounds: Unveiling the Mechanism of P-gp Inhibition

Salaroglio, Iris C;Riganti, Chiara;
2023-01-01

Abstract

The search for more effective and selective drugs to overcome cancer multidrug resistance is urgent. As such, a new series of ruthenium-cyclopentadienyl ("RuCp") compounds with the general formula [Ru(eta(5)-C5H4R)(4,4 '-R '-2,2 '-bipy)(PPh3)] were prepared and fully characterized. All compounds were evaluated toward non-small cell lung cancer cells with different degrees of cisplatin sensitivity (A549, NCI-H2228, Calu-3, and NCI-H1975), showing better cytotoxicity than the first-line chemotherapeutic drug cisplatin. Compounds 2 and 3 (R ' = -OCH3; R = CHO (2) or CH2OH (3)) further inhibited the activity of P-gp and MRP1 efflux pumps by impairing their catalytic activity. Molecular docking calculations identified the R-site P-gp pocket as the preferred one, which was further validated using site-directed mutagenesis experiments in P-gp. Altogether, our results unveil the first direct evidence of the interaction between P-gp and "RuCp" compounds in the modulation of P-gp activity and establish them as valuable candidates to circumvent cancer MDR.
2023
66
20
14080
14094
Rhutenium; lung cancer; P-glycoprotein; drug resistance
Teixeira, Ricardo G; Salaroglio, Iris C; Oliveira, Nuno F B; Sequeira, João G N; Fontrodona, Xavier; Romero, Isabel; Machuqueiro, Miguel; Tomaz, Ana Isabel; Garcia, M Helena; Riganti, Chiara; Valente, Andreia
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1945412
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