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.

FIG. 1

General overview on the role of ROS in the activity of anticancer metal drugs.

FIG. 2

Main interaction sites of anticancer metal complexes with cellular redox and oxidative stress pathways. Several metal compounds produce directly reactive oxygen species (ROS) and activate several ROS-dependent signaling and protection pathways (e.g., mediated by stress responsive transcription factors Nrf2, NF-κB, and AP-1). Sustained stress can induce apoptosis, for example, via the intrinsic mitochondrial pathway resulting in caspase-mediated cell death. Beside ROS-induced DNA damage, lipid peroxidation and protein oxidation also direct interactions with redox-regulatory mechanisms can disturb cellular redox homeostasis. Examples are the interaction of metal complexes with the thioredoxin (Trx) and glutathione (GSH) systems in the cytosol as well as in other cellular compartments such as mitochondria and endoplasmic reticulum (ER). Further, direct DNA damage by metal complexes and induction of ER stress due to accumulation of misfolded proteins can again lead to apoptosis (e.g., mediated by the transcription factors p53 and CHOP, respectively, as well as Ca²⁺ release after ER stress) and/or p53-mediated cell cycle arrests. In general, the different pathways are highly cross-linked and metal compounds target different sites. Metal complexes are indicated in bold face; cellular compartments in italic face; TrxR, thioredoxin reductase; TPx, thioredoxin peroxidases; GPx, glutathione peroxidases; GR, glutathione reductase; SOD, superoxide dismutase.

FIG. 3

Major cellular nonenzymatic antioxidants. Structures of (A) the tripeptide glutathione (built from L-glutamic acid, L-cysteine, and glycine), (B) thioredoxin (1AIU) (16), and (C) ascorbic acid.

FIG. 4

Iron-catalyzed production of hydroxyl radicals. The Haber-Weiss reaction is shown, whereby the left part depicts the Fenton reaction.

FIG. 5

Metal homeostasis in human cells. (A) Iron homeostasis: iron is accumulated in cells via transferrin-mediated endocytosis. Upon acidification iron is released from endosomal vesicles and becomes part of the labile iron pool (LIP) in the cytosol. Iron is utilized as cofactor, for example, in ribonucleotide reductases or proteins with Fe-S-clusters. Excess iron is stored in ferritin. (B) Copper homeostasis: a model of cellular copper transport and chaperoning is shown. Copper is taken up at the plasma membrane by diverse transporters (e.g., CTR1, CTR2, and DMT1). Once in the cell, copper is further distributed by intracellular chaperons. For example, copper is transported to the mitochondrial inner membrane via cox11. ATOX1 delivers excess copper to the trans-Golgi network where it is packed into vesicles by ATP7A/B and bound to ceruloplasmin for excretion. Finally, CCS chaperons copper for use in Cu/Zn-SODs.

FIG. 6

Impact of the central metal ion on the redox potential of metal complexes. As an example the cyclic voltammograms of complexes of the type M(Dp44mT)₂ with different metal centers are shown (M = manganese, iron, cobalt, nickel, copper; Dp44mT = di-2-pyridylketone 4,4-dimethylthiosemicarbazone) (33). The figure illustrates the strong impact of the central metal ion on the redox potential of structurally similar complexes.

FIG. 7

Clinically approved Pt^II drugs.

FIG. 8

General structure for terpyridine-Pt^II complexes.

FIG. 9

Pt^IV drug candidates. Tetraplatin, iproplatin, and satraplatin, together with the major reduced Pt^II-metabolite of satraplatin (JM118) are shown.

FIG. 10

Possible reduction mechanism of tetraplatin and other Pt^IV complexes. In the case of Pt^IV drugs like tetraplatin it is assumed that reduction with GSH occurs via a halide bridged electron transfer from GSH to Pt^IV resulting in GSCl and the corresponding Pt^II species. GSCl further reacts in aqueous solution with GSH yielding GSSG and HCl. Adapted from refs. (138, 210).

FIG. 11

Au^I drugs relevant for rheumatoid arthritis therapy additionally harboring anticancer activity.

FIG. 12

Experimental Au^I drugs.

FIG. 13

Experimental Au^III drugs.

FIG. 14

As^III drugs. ATO is approved for treatment of acute promyelocytic leukemia, whereas the other compounds are in (pre)clinical development.

FIG. 15

Arsenic Metabolism. (A) The classical oxidative methylation pathway of arsenic is shown involving sequential reactions of reduction and oxidative methylation steps. (B) Alternative pathway scheme for methylation of arsenic involving generation of arsenic-glutathione (GSH) complexes. From ref. (373).

FIG. 16

Ruthenium drugs. KP1019 and NAMI-A have been already evaluated in clinical trials, whereas all others are under preclinical investigation.

FIG. 17

Ligands of the best investigated anticancer Cu^II complexes.

FIG. 18

Vanadium drugs with anticancer potential.

FIG. 19

General structure of Rh^II carboxylato complexes.

FIG. 20

Vitamin B12 (Cobalamin).

FIG. 21

Anticancer cobalt compounds.

FIG. 22

Ligand release after reduction of Co^III complexes (285). In the case of Co^III complexes it is assumed that in the hypoxic tumor tissue the Co^III metal center can be reduced to Co^II, for example, by superoxide radicals. Due to the lower stability of the Co^II complexes the cytotoxic ligands are released under formation of [Co^II(H₂O₂)₆]²⁺.

FIG. 23

Manganese drugs under preclinical development as SOD mimics.

FIG. 24

Structure of Mangafodipir. This compound is in clinical use as contrast agent.

FIG. 25

Anticancer complexes with redox-silent metal centers under clinical investigation.