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

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(η-CHR)(4,4'-R'-2,2'-bipy)(PPh)] 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 and (R' = -OCH; R = CHO () or CHOH ()) 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.