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

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(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.

Qualifying P-glycoprotein in drug-resistant ovarian cancer cells: a dual-mode aptamer probe approach

“…5 The assessment of P-gp expression levels could facilitate the customization of treatment strategies, potentially guiding the selection of chemotherapeutic agents less susceptible to P-gp-mediated efflux. 6 Consequently, the quantitative detection of P-gp at the cellular level becomes particularly valuable in identifying spontaneous or transient abnormalities indicative of an underlying drug-resistance state through minimally invasive or noninvasive procedures.…”