4.7 Article

Unprecedented collateral sensitivity for cisplatin-resistant lung cancer cells presented by new ruthenium organometallic compounds

Journal

INORGANIC CHEMISTRY FRONTIERS
Volume 8, Issue 8, Pages 1983-1996

Publisher

ROYAL SOC CHEMISTRY
DOI: 10.1039/d0qi01344g

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Platinum-based therapies are the main treatment for non-small cell lung cancers (NSCLC), but multidrug resistance often leads to treatment failure. In this study, two sets of organometallic Ru(II) compounds were synthesized and tested on NSCLC cell lines, showing strong activity against cisplatin-resistant cells by inhibiting transporters MRP1 and P-gp. These compounds act as MDR-selective compounds and have the potential to enhance cisplatin cytotoxicity significantly.
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(eta(5)-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.

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