Metabolism, toxicity and anticancer activities of arsenic compounds

Abstract

A variety of studies indicated that inorganic arsenic and its methylated metabolites have paradoxical effects, namely, carcinogenic and anticancer effects. Epidemiological studies have shown that long term exposure to arsenic can increase the risk of cancers of lung, skin or bladder in man, which is probably associated with the arsenic metabolism. In fact, the enzymatic conversion of inorganic arsenic by Arsenic (+3 oxidation state) methyltransferase (AS3MT) to mono- and dimethylated arsenic species has long been considered as a major route for detoxification. However, several studies have also indicated that biomethylation of inorganic arsenic, particularly the production of trivalent methylated metabolites, is a process that activates arsenic as a toxin and a carcinogen. On the other hand, arsenic trioxide (As2O3) has recently been recognized as one of the most effective drugs for the treatment of APL. However, elaboration of the cytotoxic mechanisms of arsenic and its methylated metabolites in eradicating cancer is sorely lacking. To provide a deeper understanding of the toxicity and carcinogenicity along with them use of arsenic in chemotherapy, caution is required considering the poor understanding of its various mechanisms of exerting toxicity. Thereby, in this review, we have focused on arsenic metabolic pathway, the roles of the methylated arsenic metabolites in toxicity and in the therapeutic efficacy for the treatments of solid tumors, APL and/or non-APL malignancies.

Keywords: Acute promyelocytic leukemia; Arsenite.

Figure 1. Structures of Different Arsenic Compounds

A. Structures of As₂O₃, or B. two major forms of inorganic arsenics namely; iAs^V, iAs^III and major methylated metabolites including MMA^III, DMA^III, MMA^V and DMA^V. C. DAR and D. GSAO.

Figure 2. Proposed Arsenic Metabolism Pathway in Human

In the body, the inorganic trivalent arsenic is metabolized in a protein-bound form having successive reductive methylation by arsenicmethylatransferase (AS3MT) in the presence of glutathione and S-adenosylmethionine (SAM). In particular, monomethylarsonous acid (MMA^III), dimethylarsinous acid (DMA^III) are the trivalent intermediate metabolites which in protein-bound form are further oxidized to corresponding pentavalent monomethylarsonic acid (MMA^V) and dimethylarsinic acid (DMA^V), which are considered to be less toxic end products of arsenic metabolism.

Figure 3. Schematic Diagram Represents the Toxicities of Arsenic

Figure 4. Effects of Darinaparsin (DAR) on Cellular Functions

Production of intracellular ROS is the key events of DAR mediated apoptosis. Generally, it occurs through either by the activation of NADPH oxidase complex or direct effect on mitochondrial membrane potential. Abnormal mitochondrial functions are associated with the release of cytochrome c resulting in the activation of apoptosome, which causes initiation of apoptosis. The ultimate result is cell cycle arrest, induction of apoptosis and anti-angiogenic activity.

Figure 5. Molecular mechanism of GSAO

GSAO is activated by tumor γGT at the cell surface, and the following GCAO is transported across the plasma membrane by the organic anion transporting polypeptide (OATP). Additionally, GCAO is possibly further processed to CAO by dipeptidase in the cytosol and finally reacts with ANT of the inner mitochondrial membrane.

Figure 6. Toxicity and Anticancer Effects of MMA

III and DMAIII. MMA^III specifically inhibit the activity of complexes II and IV, which results in electron leakage from complex I and III causing the generation of ROS in mitochondria, resulted in induction of mitochondrial dysfunction and release Cyt c, finally inducing apoptosis through caspase-3 dependent pathway. DMA^III predominantly target ER, stimulating the activation of PERK whose activation leads to the phosphorylation of eIF-2α, translation initiation of ATF4 and CHOP, resulting in induction of apoptosis. Similarly, DMA^III-induced ER-stress also activate IRE1, this activation of IRE1 further forms a complex with TRAF2 recruiting ASK1, which in turns activates JNK to induce apoptosis.

Figure 7. Molecular Mechanisms of iAs

^III and its Trivalent Methylated Metabolites (i.e., MMA^III and DMA^III) Induced Cell Differentiation and Apoptosis in APL Cells. Arsenic trioxide in hydrolyzed form, i.e., iAs^III may cause formation of PML-RARα protein multimers, initiate the nucleation of PML-NBs, enhanced SUMOylation/ubiquitination, resulting degradation of PML-RARα fusion protein by ubiquitin/proteasome pathway, finally promoting cell differentiation leading to clinical remission. On the other hand, MMA^III and DMA^III have shown no effect on induction of PML-RARα protein degradation and APL cell differentiation. Conversely, they have strong effect on induction of apoptosis in APL cells through mitochondria and ER-dependent pathways.