NKP-1339 is the first-in-class ruthenium-based anticancer drug in clinical development against solid cancer and has recently been studied successfully in a phase I clinical trial. Ruthenium compounds such as KP1019 (indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]) and NKP-1339 (the sodium salt analogue of KP1019, sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]) have a high tumour targeting potential based (1) on their strong binding to serum proteins such as albumin and transferrin as well as (2) on their activation in the reductive tumour milieu. The redox activity of ruthenium compounds is believed to represent one major mode of action leading to disturbance of the cellular redox balance and, consequently, induction of G₂/M cell cycle arrest, blockage of DNA synthesis, and induction of apoptosis via the mitochondrial pathway. Moreover, potent synergistic activities of NKP-1339 with the clinically approved tyrosine kinase inhibitor sorafenib were recently reported in vitro and in vivo. Taken together, KP1019 and NKP-1339 are promising drug candidates, and especially the very limited side effects observed so far in clinical phase I trials seem to be a major advantage of this class of ruthenium drugs as compared to other chemotherapeutics and targeted anticancer compounds.

Cells require tight regulation of the intracellular redox balance and consequently of reactive oxygen species for proper redox signaling and maintenance of metal ( e.g. , of iron and copper) homeostasis. In several diseases, including cancer, this balance is disturbed. Therefore, anticancer drugs targeting the redox systems, for example, glutathione and thioredoxin, have entered focus of interest. Anticancer metal complexes (platinum, gold, arsenic, ruthenium, rhodium, copper, vanadium, cobalt, manganese, gadolinium, and molybdenum) have been shown to strongly interact with or even disturb cellular redox homeostasis. In this context, especially the hypothesis of “activation by reduction” as well as the “hard and soft acids and bases” theory with respect to coordination of metal ions to cellular ligands represent important concepts to understand the molecular modes of action of anticancer metal drugs. The aim of this review is to highlight specific interactions of metal-based anticancer drugs with the cellular redox homeostasis and to explain this behavior by considering chemical properties of the respective anticancer metal complexes currently either in (pre)clinical development or in daily clinical routine in oncology. Antioxid. Redox Signal. 15, 1085–1127.

Significance: During the last decades, thiosemicarbazones have been clinically developed for a variety of diseases including tuberculosis, viral infections, malaria and cancer. With regard to malignant diseases, the class of α-N-heterocyclic thiosemicarbazones, and here especially Triapine, was intensively developed in multiple clinical phase I/II trials. Recent Advances: Very recently two new derivatives, namely COTI-2 and DpC have entered phase I evaluation. Based on the strong metal-chelating/metal-interacting properties of thiosemicarbazones, interference with the cellular iron (and copper) homeostasis is assumed to play an important role in their biological activity. Critical Issues: In this review, we summarize and analyze the data on the interaction of (α-N-heterocyclic) thiosemicarbazones with iron, with the special aim to bridge the current knowledge on their mode of action from chemistry to (cell) biology. In addition, we highlight the difference to classical iron(III) chelators such as desferrioxamine (DFO) which are used for the treatment of iron overload. Future Directions: We want to emphasize that thiosemicarbazones are not solely removing iron from the cells/organism. In contrast, they should be considered as iron-interacting drugs influencing diverse biological pathways with a complex and multi-facetted mode of action. Consequently, in addition to the discussion of physicochemical properties (e.g. complex stability, redox activity), this review contains an overview on the diversity of cellular thiosemicarbazone targets and drug resistance mechanisms.