Multi-action Pt(IV) anticancer agents; do we understand how they work?

Pt(IV) complexes act as prodrugs that are activated inside cancer cells releasing cytotoxic Pt(II) drugs such as cisplatin as well as two axial ligands. These ligands can be used to confer favorable pharmacological properties to the prodrug. They can be innocent spectators, targeting agents or bioactive moieties. When the ligands are bioactive moieties such as enzyme inhibitors or antiproliferative agents, the prodrug attacks several cellular targets at the same time acting as a multi-action prodrug. These compounds are very potent and often overcome resistance to cisplatin. Despite solid rationalization and careful design, often there is no correlation between the ability of the bioactive ligand to inhibit the target enzyme and the cytotoxicity. This might be because most bioactive ligands affect several cellular functions and not only the ones they were designed to inhibit. Thus, even "dual action" prodrugs might in reality be multi-action prodrugs. This class of multi-action Pt(IV) prodrugs seems to have great potential in the attempts to overcome resistance.