François Rieger, CEO, and Carole Nicco, Chief Scientific Officer, BioSenic, looks at the use of Arsenic as a novel API as a companion piece to our latest EPM Issue.
There are a number of novel APIs which are starting to make serious clinical advances. The use of a combined metalloid/metal treatment as an anti-inflammatory, immunomodulatory, and anti-fibrotic API is a new concept. This new type of nonsteroidal anti-inflammatory drugs (NSAIDs) with anticancer activity could potentially lead to a first-in-class medication and a curative therapy for severe autoimmune diseases, rather than the currently available palliative treatments to slow progression.
Modern scientific and therapeutic applications of arsenic trioxide (As2O3 or ATO) started in the 1990s in the treatment of acute promyelocytic leukaemia (APL) with striking efficacy and a good safety profile (Shen et al., 1997; Wang et al., 2008). So far, ATO, in a first step combined with all-trans retinoic acid (ATRA), and as a standalone has revolutionised the treatment of APL (Lo-Coco et al., 2013; Cicconi et al., 2016). Since 2002, Arsenic Trioxide (ATO, As2O3) has been investigated and used in the treatment of various types of leukaemia including chronic myeloid leukaemia (CML) and acute promyelocytic leukaemia. Not all the mechanisms triggered by Arsenic are known as yet, but Arsenic has been shown to have a clear selective effect on activated immune cells when used for short exposures (weeks) at low doses. The cytokines secreted by the targeted immune cells are able to modulate the differentiation of other types of cells, such as fibroblasts into myofibroblasts (Luo et al. 2014). At low doses, arsenic's anti-inflammatory properties far outweigh its potential toxicity when used at medically low doses (micromolar blood concentrations) for short, defined periods of time (weeks).
Arsenic is clearly involved in:
- Pro-apoptotic mechanisms, mainly due to the generation of oxidative stress.
- Metabolic modulations.
- Epigenetic modifications.
- Bi-directional regulation on inflammasomes, which is probably tissue dependent.
Therefore, arsenic has a selective action from metabolism to the epigenetic status of the cells, with redox as a keystone reaction. Arsenic is found to generally have a beneficial action on many different types of immune cells in both the innate and the adaptive response. It potentiates a return to homeostasis, otherwise to apoptosis when this is no longer possible.
In recent decades, the successful results of ATO treatment in mouse models of several autoimmune and inflammatory diseases have shed new light on this drug as a novel immunomodulator (Bobe et al., 2006; Kavian et al., 2012a; 2012b). ATO has been evaluated by Medsenic/BioSenic in mouse models of autoimmune and pro-fibrotic diseases such as Graft-versus-Host Disease (GvHD), Systemic Lupus Erythematosus (SLE) and Systemic Scleroderma (SSc). The results are clear: low-dose ATO has been shown to cure these diseases in preclinical models.
Safety has also been evaluated in phase II human clinical trials in cGvHD and lupus being conducted by Medsenic/BioSenic. The mechanism of action of ATO is clear at low doses and short times of exposure. However, arsenic at high doses can also react with the sulfhydryl group (also called “thiol group”) on many proteins. The thiol group is ubiquitous in our body and mostly found in the oxidised form as disulfide linkages. The disulfide linkages are generally key to the tertiary and quaternary structures of proteins. ATO has high affinity for sulfhydryl groups and can react with reduced cysteines in peptides and proteins. Thus, arsenic binding to a specific protein can alter the conformation of the protein, resulting in loss or gain of function, and affect its recruitment of and interaction with other proteins and DNA. Arsenic chemical activity at high doses and prolonged time of administration in vivo can influence many different biological pathways among which:
- Proteins and enzymes implicated in metabolism (Pyruvate Dehydrogenase, glucose oxidase…).
- Enzymes implicated in redox status, mitochondrial functions and oxidative stress modulation.
- DNA Repair Enzymes.
- Post-translational modification that facilitates the SUMOylation and subsequent degradation of target proteins.
- Direct binding of Arsenic to cysteine residues in zinc fingers.
All these mechanisms of action can happen in various types of cells. However, arsenic will also depend on the pathways by which it enters the cells before triggering the above mechanisms. The expression of certain pores on the surface of the cells will determine its rapid action on the cell under consideration. Once in the cells, depending on the intracellular activity and the redox status, arsenic may act with greater or lesser efficacy on different activated signalling or regulatory pathways involved in cell differentiation and/or activation.
Arsenic has very original pharmacological properties and can be further used with other ions implicated in the cell’s redox status, namely Fenton and Fenton-like ions. BioSenic believes that the use of arsenic at low doses in combination with other potentiating ions has important positive aspects, among which the fact that it only acts on abnormal over -stimulated pathways. Therefore, Medsenic/BioSenic recently combined ATO with copper (Cu, metal), a divalent cation, contributing to generate a moderate Fenton-like reaction in order to potentiate the depletion of activated immune cells through the reactive oxygen species (ROS)-mediated effects of Arsenic (Chêne et al. 2022). In fact, the combined treatment of ATO and Cu allowed a significant reduction in ATO dose while maintaining the same overall biological activity. In cGvHD and SSc mouse models, the combination affects both macrophages and fibroblasts, reducing inflammation and fibrosis (Chêne et al. 2022; Chêne et al. 2023). More specifically, the beneficial combination of Cu with ATO reduces B lymphocyte cytokine and chemokine production and inflammation, modulates macrophage phenotype, and decreases the number of activated dendritic cells.
ATO combined with Cu related excipients will be a real benefit to treat pathologies characterised by activated cells, sensitive to an increase in oxidative stress. These include autoimmune diseases, inflammatory diseases, and the oxidative burst induced by a violent immune response. Autoimmune diseases have one thing in common: an inappropriate response of the immune system to components of the self. Today, patients suffering from these autoimmune diseases have access only to palliative treatments to slow their progression, but they remain incurable. The ATO-Cu combination is an innovative, curative therapy for severe autoimmune diseases.
Legend
Non exhaustive intracellular mechanisms of action of the combination of low-dose ATO associated with copper ions. (created by Carole Nicco with Biorender) Depending on the cell type, the activated signalling pathways and the time of action, different responses are observed. ATO has been shown to be anti-inflammatory and, as copper, can modulate the redox status. Combined in a treatment, arsenic and copper can influence inflammation, cellular redox state, apoptosis and cuproptosis.