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(η5-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.