Anticancer activity of small-molecule and nanoparticulate arsenic(III) complexes

Abstract

Starting in ancient China and Greece, arsenic-containing compounds have been used in the treatment of disease for over 3000 years. They were used for a variety of diseases in the 20th century, including parasitic and sexually transmitted illnesses. A resurgence of interest in the therapeutic application of arsenicals has been driven by the discovery that low doses of a 1% aqueous solution of arsenic trioxide (i.e., arsenous acid) lead to complete remission of certain types of leukemia. Since Food and Drug Administration (FDA) approval of arsenic trioxide (As2O3) for treatment of acute promyelocytic leukemia in 2000, it has become a front-line therapy in this indication. There are currently over 100 active clinical trials involving inorganic arsenic or organoarsenic compounds registered with the FDA for the treatment of cancers. New generations of inorganic and organometallic arsenic compounds with enhanced activity or targeted cytotoxicity are being developed to overcome some of the shortcomings of arsenic therapeutics, namely, short plasma half-lives and a narrow therapeutic window.

Figure 1

Structure of major arsenic ores. A) Orpiment. B) Realgar. C) Arsenic trioxide or “white arsenic”. ^,

Figure 2

Structures of relevant arsenic compounds.

Figure 3

Proposed structure of arsenic-glutathione complexes.

Figure 4

Proposed mechanisms of action for arsenic trioxide. Arsenous acid enters mammalian cells either by passive diffusion, or by the neutral solute transporter proteins in the aquaporin family.^{, , ,} It then binds to the numerous thiol moieties present in the cell, particularly glutathione, the interaction of which is catalyzed by glutathione s-transferase. Arsenous acid can bind to microtubules, preventing depolymerization and halting the cell cycle. Arsenic also binds to the active site of thioredoxin reductase, which in turn causes the buildup of oxidized, mis-folded proteins in the cell. In acute promyelocytic leukemia, arsenic binds to a zinc finger fusion protein, PML/RARα, which causes aggregation and degradation of the protein.^, Arsenic can be metabolized into methylarsonic acid or dimethylarsinic acid. Arsenic interacts with mitochondrial proteins to collapse the mitochondrial membrane potential, produce reactive oxygen species (ROS), release cytochrome c into the cytoplasm and initiate apoptosis.

Figure 5

Mechanism of PML/RARα degradation. It is unclear in which order these processes occur, however, arsenous acid may induce crosslinking between PML/RARα dimers which results in a conformational change, or it may induce a conformational change in PML/RARα dimers that causes aggregation. The fate of the aggregated PML/RARα is degradation in the proteasome, which results in cell death or differentiation. Inset, the change of coordination geometry when arsenic is bound to the RING domain of PML (orange) compared to the zinc binding (blue).^{, ,}

Figure 6

Arsenic sulfide nanogel assembly is driven by coordination of the arsenic centers by nitrogen ligands and hydrogen bonds between the chelator molecules.

Figure 7

Preparation and use of arsenic nanobins. Top: Synthesis scheme of arsenic nanobins. M = Ni²⁺, [Pt(NH₃)₂(OH₂)₂]²⁺ A)Tumor volume plot of human triple-negative orthotopic xenograft tumors implanted in the 4^th mammary fat pad of female nude mice showing decreased tumor volume in nanobin treated mice vs. mice treated with arsenic trioxide. B) Nanobin treatment increases total amount of arsenic in the tumor compared to arsenic trioxide treatment. C) Stable animal weight during treatment indicates all treatments were well tolerated.

Figure 8

Structure of supramolecular complex including arsenic-nickel coordination.

Figure 9

Structure of Arsenoplatin 1 based on single-crystal X-ray crystallography. Unlabeled atoms are colored according to the key in Figure 8.

Scheme 1

Stability of the As-Pt bond in Arsenoplatin 1. The strong trans effect of As enables rapid displacement of the chloride ligand with thiocyanate. Both the thiocyanate and isothiocyanate species are present in DMSO.