Anticancer Activity of Metal Complexes: Involvement of Redox Processes

Abstract

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. I. Introduction II. Redox Processes in Living Organisms A. Mammalian redox metabolism B. Cellular response to oxidative stress and resistance to metal compounds C. Fenton chemistry in biological context III. Homeostasis of Redox Active Metals in Mammalians A. Iron homeostasis 1. Iron transport 2. Intracellular iron proteins B. Copper homeostasis IV. From Electrochemistry to Cellular Redox Reactions and Anticancer Therapy A. Oxidation and reduction: the principles of redox processes B. The impact of metal and ligand on redox potentials C. Anticancer metal compounds and redox processes: overview V. Metal-Based Anticancer Drugs and Their Redox-Related Modes of Action A. Platinum 1. Platinum(II) 2. Platinum(IV) B. Gold 1. Gold(I) 2. Gold(III) C. Arsenic D. Ruthenium E. Copper F. Vanadium G. Rhodium H. Cobalt I. Manganese J. Complexes with redox silent metal centers in clinical trials VI. Conclusion