A Fenton-like cation can improve arsenic trioxide treatment of sclerodermatous chronic Graft-versus-Host Disease in mice

Chêne, Charlotte; Jeljeli, Mohamed; Rongvaux-Gaïda, Dominique; Thomas, Marine; Rieger, François; Batteux, Frédéric; Nicco, Carole

doi:10.3389/fimmu.2022.917739

Cited by 4 publications

(8 citation statements)

References 53 publications

(63 reference statements)

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“…With regard to the results obtained in a previous work published in Frontiers in Immunology ( 14 ), we chose the lowest copper concentration that modified the GSH concentration and the survival rate in tumor cells. This choice was also determined by the fact that we wanted to use the lowest dose to avoid toxicity in animals.…”

Section: Discussionmentioning

confidence: 99%

“…These results are similar to those of previous studies by Kavian et al., who showed that ATO decreased skin fibrosis in a mouse model of chronic cGvHD and in the mouse model of SSc ( 7 , 24 ). Furthermore, we recently demonstrated that CuCl 2 potentiates the therapeutic effect of low-dose ATO alone on skin fibrosis in a mouse model of sclerodermatous cGvHD ( 14 ). In humans, an effective dose (0.16 mg/kg) can induce side effects such as skin reactions, gastrointestinal disorders and a reversible increase in transaminases, leading to discontinuation of treatment ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

“…Preliminary tests showed that a high dose of CuCl 2 (4 µg/g) alone is toxic for mice (data not shown). Finally, a low dose of CuCl 2 , equivalent to doses used in food supplements, potentiated the effect of a low dose of ATO (2.5 µg/g) to the same level as that of a high dose of ATO (5 µg/g), as studied in a mouse model of cGvHD (14). Therefore, we used the CuCl 2 0.5 µg/g dosage.…”

Section: Treatment Of Ssc Micementioning

confidence: 99%

“…The production of ROS by these reactions is known to induce a strong oxidative stress in activated cells leading to their apoptotic death (11)(12)(13). We have previously tested several divalent cations (copper, iron, manganese, gold, zinc) for their ability to potentiate in vitro the pro-oxidative effect of ATO on human and murine cancer cells (14). Among them Cu 2+ (in its CuCl 2 molecular form) showed the most significant effects on the induction of oxidative stress and apoptosis of cancer cells when used along with ATO.…”

Section: Introductionmentioning

confidence: 99%

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Optimal combination of arsenic trioxide and copper ions to prevent autoimmunity in a murine HOCl-induced model of systemic sclerosis

Chêne

Rongvaux-Gaïda²,

Thomas

et al. 2023

Front. Immunol.

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IntroductionSystemic sclerosis (SSc) is a rare chronic autoimmune disease characterized by diffuse fibrosis of the skin and internal organs and vascular abnormalities. The etiology and physiopathology are complex due to the heterogeneity of its overall clinical presentation. Arsenic trioxide (ATO) has been proven to be effective against SSc, sclerodermatous Graft-versus-Host Disease, multiple sclerosis, Crohn’s disease or systemic lupus erythematosus animal models and has demonstrated promising effects in human clinical trials. Its efficacy was shown to be related at least in part to the generation of Reactive Oxygen Species (ROS) and the selective deletion of activated immune cells and fibroblasts. However, ATO can induce some adverse effects that must be considered, especially when used for the treatment of a chronic disease.MethodsWe evaluate here, in vitro and in a mouse model of SSc, the improved efficacy of ATO when associated with a Fenton-like divalent cation, namely copper chloride (CuCl2), also known to trigger the production of ROS.ResultsIn preliminary experiments in vitro, ATO 1 µM + CuCl2 0.5 µM increased ROS production and increased apoptosis of NIH 3T3 murine fibroblasts compared to 1 µM ATO alone. In vivo, in the HOCl-induced mouse model of SSc, co-treatment with ATO 2.5 μg/g + CuCl2 0.5 μg/g significantly alleviated clinical signs such as the thickening of the skin (p<0.01) and cutaneous fibrosis, in a manner equivalent to treatment with ATO 5 µg/g. Our results provide evidence that co-treatment with ATO 2.5 μg/g + CuCl2 0.5 μg/g decreases the number of B cells and the activation of CD4+ T lymphocytes. The co-treatment substantially blocks the NRF2 signaling pathway, increases H2O2 production and results in the improvement of the health status of mice with experimental SSc.ConclusionIn conclusion, copper combined with ATO treatment halved the concentration of ATO needed to obtain the same effect as a high dose of ATO alone for the treatment of SSc mice. The strategy of using lower doses of drugs with different mechanisms of action in combination has many potential advantages, the first being to lessen the potential side effects induced by ATO, a drug with side effects quickly increased with dosage.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Treatment Of Ssc Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Optimal combination of arsenic trioxide and copper ions to prevent autoimmunity in a murine HOCl-induced model of systemic sclerosis

Chêne

Rongvaux-Gaïda²,

Thomas

et al. 2023

Front. Immunol.

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“…More than 50 million people from West Bengal and Bangladesh were exposed to arsenic levels above 50 μg/L, which caused frequent arsenic poisoning and adverse effects on human health . A growing body of literature suggests that arsenic disrupts a series of cellular processes, including oxidative stress, cell proliferation, inflammation, and autophagy and apoptosis. ,− Arsenic exposure can lead to many adverse health effects of diabetes mellitus (DM), − skin lesions, , kidney disease, , neurological impairment, , cancers, , male reproductive injury, and cardiovascular disease (CVD) as cardiac arrhythmias, endothelial dysfunction, and ischemic heart failure. , …”

Section: Introductionmentioning

confidence: 99%

The Role of microRNAs in Arsenic-Induced Human Diseases: A Review

Liu,

Lei

2023

J. Agric. Food Chem.

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MicroRNAs (miRNAs) are noncoding RNAs with 20–22 nucleotides, which are encoded by endogenous genes and are capable of targeting the majority of human mRNAs. Arsenic is regarded as a human carcinogen, which can lead to many adverse health effects including diabetes, skin lesions, kidney disease, neurological impairment, male reproductive injury, and cardiovascular disease (CVD) such as cardiac arrhythmias, ischemic heart failure, and endothelial dysfunction. miRNAs can act as tumor suppressors and oncogenes via directly targeting oncogenes or tumor suppressors. Recently, miRNA dysregulation was considered to be an important mechanism of arsenic-induced human diseases and a potential biomarker to predict the diseases caused by arsenic exposure. Endogenic miRNAs such as miR-21, the miR-200 family, miR-155, and the let-7 family are involved in arsenic-induced human disease by inducing translational repression or RNA degradation and influencing multiple pathways, including mTOR/Arg 1, HIF-1α/VEGF, AKT, c-Myc, MAPK, Wnt, and PI3K pathways. Additionally, exogenous miRNAs derived from plants, such as miR-34a, miR-159, miR-2911, miR-159a, miR-156c, miR-168, etc., among others, can be transported from blood to specific tissue/organ systems in vivo. These exogenous miRNAs might be critical players in the treatment of human diseases by regulating host gene expression. This review summarizes the regulatory mechanisms of miRNAs in arsenic-induced human diseases, including cancers, CVD, and other human diseases. These special miRNAs could serve as potential biomarkers in the management and treatment of human diseases linked to arsenic exposure. Finally, the protective action of exogenous miRNAs, including antitumor, anti-inflammatory, anti-CVD, antioxidant stress, and antivirus are described.

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Arsenic trioxide demonstrates efficacy in a mouse model of preclinical systemic sclerosis

Cauvet,

Decellas,

Guignabert

et al. 2023

Arthritis Res Ther

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Background Uncontrolled T-cell activation plays a key role in systemic sclerosis (SSc). Arsenic trioxide (ATO) has immunological effects and has demonstrated potential in preclinical SSc models. In this study, we assessed the efficacy of ATO in Fra2 transgenic (Fra2TG) mice, which develop severe vascular remodeling of pulmonary arterioles and nonspecific interstitial pneumonia-like lung disease, closely resembling human SSc-associated pulmonary hypertension, therefore partially resembling to the SSc human disease. Methods The efficacy of ATO in Fra2TG mice was evaluated through histological scoring and determination of cell infiltration. Fibrotic changes in the lungs were assessed by measuring collagen content biochemically, using second harmonic generation to measure fibrillar collagen, and imaging via computed tomography. Cardiovascular effects were determined by measuring right ventricular systolic pressure and vessel remodeling. The mechanism of action of ATO was then investigated by analyzing lung cell infiltrates using flow cytometry and bulk RNA with sequencing techniques. Results After ATO treatment, the Ashcroft histological score was substantially decreased by 33% in ATO-treated mice compared to control mice. Other investigations of fibrotic markers showed a trend of reduction in various measurements of fibrosis, but the differences did not reach significance. Further cardiovascular investigations revealed convergent findings supporting a beneficial effect of ATO, with reduced right ventricular systolic pressure and medial wall thickness, and a significant decrease in the number of muscularized distal pulmonary arteries in ATO-treated Fra2TG mice compared to untreated Fra2TG mice. Additionally, inflammatory cell infiltration was also markedly reduced in lesioned lungs. A reduction in the frequency of CD4 + and T effector memory cells, and an increase in the percentage of CD4 + T naive cells in the lungs of ATO-treated Fra-2TG mice, was observed when compared to PBS group Fra-2Tg mice. RNA-seq analysis of ATO-treated mouse lungs revealed a downregulation of biological pathways associated with immune activity and inflammation, such as T-cell activation, regulation of leucocyte activation, leucocyte cell–cell adhesion, and regulation of lymphocyte activation. Conclusions Our results suggest the clinical relevance of ATO treatment in SSc. Using the Fra2TG mouse model, we observed significant lung histological changes, a trend towards a decrease in various fibrotic makers, and a strong reduction in vascular remodeling. The mechanism of action of ATO appears to involve a marked counteraction of the immune activation characteristic of SSc, particularly T-cell involvement. These findings pave the way for further studies in SSc.

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A Fenton-like cation can improve arsenic trioxide treatment of sclerodermatous chronic Graft-versus-Host Disease in mice

Cited by 4 publications

References 53 publications

Optimal combination of arsenic trioxide and copper ions to prevent autoimmunity in a murine HOCl-induced model of systemic sclerosis

Optimal combination of arsenic trioxide and copper ions to prevent autoimmunity in a murine HOCl-induced model of systemic sclerosis

The Role of microRNAs in Arsenic-Induced Human Diseases: A Review

Arsenic trioxide demonstrates efficacy in a mouse model of preclinical systemic sclerosis

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