Ruthenium-Based Anticancer Compounds: Insights into Their Cellular Targeting and Mechanism of Action

The identification of the mode of action of a drug is mandatory for the development of clinically effective chemotherapeutics. Ruthenium complexes hold potential as alternatives to platinum drugs in cancer chemotherapy. In spite of their great importance, their mechanisms of action have not yet been fully elucidated. Inspired by platinum-based drugs, for which the main cellular target involved in their mode of action is DNA, the first approach in the elucidation of the mechanism by which anticancer ruthenium drugs exert their effect was directed toward DNA interactions. It soon became clear that the extent of binding to DNA and the mechanism of interaction did not correlate properly with their cytotoxicity. Moreover, complexes that are structurally similar exhibit a quite different effect both in vitro and in vivo, for example, Ru(III) NAMI-A and KP1019 and the reverse, that is, complexes that are structurally different as in the case of NAMI-A and RAPTA-T, have similar in vitro and in vivo behavior. The potential of ruthenium-based metallodrugs in cancer chemotherapy is also highlighted by the fact that many of these agents are active against cancers that are not responsive to platinum drugs. This feature suggests that ruthenium complexes exert their effect through a route different from that of platinum, and, importantly, their spectrum of action is expected to be broader. Research so far identified several targets of different nature that might be involved. Herein, plausible mechanisms of action of Ru-based anticancer compounds highlight their interactions with different biological targets. In particular, hints to the mode of action of a new family of “RuII(η5-C5H5)” complexes showing an emergent high anticancer potential is discussed in some detail and possible pathways for their action are disclosed.