Fast pH‐Driven Solubilization Method of Realgar (As <sub>4</sub> S <sub>4</sub> ) to Reduce the Toxicity of Arsenic [As(III)] for Medicinal Purposes

Acute promyelocytic leukemia (APL) accounts for 5-15% of acute myeloid leukemia cases. It is typically characterized by the (15;17) chromosomal translocation, producing the pathogenic retinoic acid receptor (RAR) alpha/promyelocytic leukemia (PML) fusion protein. Recently, remission of APL has been achieved using the first chemotherapy-independent oral drug regimen in anticancer therapy, consisting of all-trans retinoic acid (targeting RARalpha) and the arsenic sulfide realgar (targeting PML). However, clinical adoption of realgar and the characterization of its active breakdown products have been hampered by its poor solubility. Here, a scalable pH/temperature-based process is described that partially mimics gut transition, achieving fast and reproducible solubilization of realgar. Six different spectroscopic and spectrometric techniques are employed to investigate solubilized realgar. Furthermore, it is shown that solubilized realgar targets PML, displaying wider in vitro therapeutic indices and lower off-target effects than arsenic trioxide, the current APL standard of care. Moreover, in line with evidence of an interplay between PML and HIV persistence, solubilized realgar can disrupt HIV latency, the main barrier to an HIV/AIDS cure, in CD4 T cells of people living with HIV. These findings may open avenues for streamlining realgar solubilization and designing less toxic, orally administrable arsenic-based therapies.

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Publication Details

Journal
Advanced Science
Published
2025-04-24
DOI
https://doi.org/10.1002/advs.202502740
Primary Topic
Arsenic contamination and mitigation
Type
article
Field-Weighted Citation Impact
0.00

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article

Fast pH‐Driven Solubilization Method of Realgar (As 4 S 4 ) to Reduce the Toxicity of Arsenic [As(III)] for Medicinal Purposes

Jochen H. Kurz, Hugo P. Monteiro, Marina Lušić, Alceu T. Silveira et al.
Advanced Science
Arsenic contamination and mitigation
article

Fast pH‐Driven Solubilization Method of Realgar (As 4 S 4 ) to Reduce the Toxicity of Arsenic [As(III)] for Medicinal Purposes

Jochen H. Kurz, Hugo P. Monteiro, Marina Lušić, Alceu T. Silveira, Iart Luca Shytaj, Douglas S. Franciscato, Teresa Dallinger, Lara Gallucci, Helton Pereira Nogueira, Mattia Forcato, Mohammad Tarek, Mahmoud ElHefnawi, Andrea Savarino, Ricardo Sobhie Diaz, Bojana Lucic, M. Ismail, Danilo Dias, Maytê S. Toledo, Merrel Robinson, Jessica Dias da Silva Ferraz, Claudia Gutfleisch
article en

Abstract

Acute promyelocytic leukemia (APL) accounts for 5-15% of acute myeloid leukemia cases. It is typically characterized by the (15;17) chromosomal translocation, producing the pathogenic retinoic acid receptor (RAR) alpha/promyelocytic leukemia (PML) fusion protein. Recently, remission of APL has been achieved using the first chemotherapy-independent oral drug regimen in anticancer therapy, consisting of all-trans retinoic acid (targeting RARalpha) and the arsenic sulfide realgar (targeting PML). However, clinical adoption of realgar and the characterization of its active breakdown products have been hampered by its poor solubility. Here, a scalable pH/temperature-based process is described that partially mimics gut transition, achieving fast and reproducible solubilization of realgar. Six different spectroscopic and spectrometric techniques are employed to investigate solubilized realgar. Furthermore, it is shown that solubilized realgar targets PML, displaying wider in vitro therapeutic indices and lower off-target effects than arsenic trioxide, the current APL standard of care. Moreover, in line with evidence of an interplay between PML and HIV persistence, solubilized realgar can disrupt HIV latency, the main barrier to an HIV/AIDS cure, in CD4 T cells of people living with HIV. These findings may open avenues for streamlining realgar solubilization and designing less toxic, orally administrable arsenic-based therapies.

Advanced ScienceVol. 12(29)
University of Padua (IT), Universidade de São Paulo (BR), Heidelberg University (DE), University Hospital Heidelberg (DE), University of Bristol (GB), German Center for Infection Research (DE), Armed Forces College of Medicine (EG), National Research Centre (EG), Universidade Federal de São Paulo (BR)
Deutsches Zentrum für Infektionsforschung, UK Research and Innovation, University of Bristol, Deutsche Forschungsgemeinschaft, Fundação de Amparo à Pesquisa do Estado de São Paulo, Medical Research Council, Engineering and Physical Sciences Research Council
Good health and well-being
Openalex Percentile: Top 92%
Arsenic contamination and mitigation
DOIOpen Access PDFOpenAlex
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