Unprecedented collateral sensitivity for cisplatinresistant lung cancer cells presented by new ruthenium organometallic compounds

Abstract

Platinum-based therapies continue to be the main regimen used to treat non-small cell lung cancers (NSCLC), where multidrug resistance plays a key role in treatment failure and strategies to overcome this limitation are urgently sought for. In view to contribute to the development of this field, two sets of new organometallic Ru(II) compounds with general formula [Ru(η5-C5H4R')(bipyR)(PPh3)][CF3SO3], where R' = CHO or CH2OH and bipyR = 2,2'-bipyridine (1, 5), 4,4'-dimethyl-2,2'-bipyridine (2, 6), 4,4'-di(hydroxymethyl)- 2,2'-bipyridine (3, 7) and 4,4'-dibiotin ester-2,2'-bipyridine (4), were synthesized and fully characterized. All compounds were tested against four types of NSCLC cell lines (A549, NCI-H228, Calu-3 and NCI-H1975), and four of them (1, 2, 4 and 6) presented a strong activity against cisplatin-resistant NSCLC cells. They were also able to increase cisplatin cytotoxicity up to 1390-fold (when administrated at nontoxic doses) by inhibiting MRP1 and P-gp transporters. Given the role of MRP1 in cisplatin resistance, in particular in lung cancer where cisplatin is the first-line treatment, the finding that these compounds are inducers of collateral sensitivity is of particular relevance. As far as we are aware, these are the first ruthenium- based compounds with such a mechanism of action, taking advantage of an 'Achilles' heel' and acting as MDR-selective compounds