Despite major advances in diagnosis and therapy, lung cancer is still the leading cause of cancer‑related deaths worldwide, whereas non-small cell lung cancer (NSCLC) represents the most frequent type of lung cancer accounting for 85–90% of all cases diagnosed. The (multi‑)chemotherapeutic regimens used to treat NSCLC, often centered in platinum-based and purely organic drugs, have limited success mainly due to intrinsic and/or acquired treatment resistance. Over the past decades, several ruthenium-based compounds have been explored for their medicinal applications and their potential acknowledged as promising alternatives to efficiently treat a wide range of cancers.

Our research group has been focused on exploring metal-based compounds, especially incorporating the “ruthenium-cyclopentadienyl” (“RuCp”) scaffold. This moiety is an appealing and robust scaffold to build new molecules from where the judicious choice of co-ligands allows to impart different properties and to fine-tune the performance of the whole complex. In this frame, we developed new compounds based on the functionalized “RuCp” moiety containing bipyridyl ligands which displayed strong activity against four NSCLC cell lines (A549, NCI-H228, Calu-3 and NCI-H1975). Our preliminary results show that the compounds are more cytotoxic in cisplatin-resistant than in cisplatin-sensitive cells, and increased cisplatin cytotoxicity by inhibiting MRP1 and P-gp transporters. This work unveils the mechanism of action of these compounds, suggesting that drug efflux transporters could be a potential target, and, more importantly, indicates that they induce collateral sensitivity in cisplatin-resistant lung cancer cells.