Fast pH‐Driven Solubilization Method of Realgar (As4S4) to Reduce the Toxicity of Arsenic [As(III)] for Medicinal Purposes
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...
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Wiley
2025-08-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202502740 |
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| author | Bojana Lucic Douglas Santana Franciscato Helton Pereira Nogueira Lara Gallucci Alceu Totti Silveira Junior Asmaa Mohamed Ismail Millie Robinson Teresa Dallinger Claudia Gutfleisch Jochen Kurz Maytê Toledo Jessica Dias da Silva Ferraz Mohammad Tarek Danilo Dias Ricardo Sobhie Diaz Mahmoud ElHefnawi Mattia Forcato Hugo P Monteiro Marina Lusic Iart Luca Shytaj Andrea Savarino |
| author_facet | Bojana Lucic Douglas Santana Franciscato Helton Pereira Nogueira Lara Gallucci Alceu Totti Silveira Junior Asmaa Mohamed Ismail Millie Robinson Teresa Dallinger Claudia Gutfleisch Jochen Kurz Maytê Toledo Jessica Dias da Silva Ferraz Mohammad Tarek Danilo Dias Ricardo Sobhie Diaz Mahmoud ElHefnawi Mattia Forcato Hugo P Monteiro Marina Lusic Iart Luca Shytaj Andrea Savarino |
| author_sort | Bojana Lucic |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ca8daa10701047cd986ead9e1edb2d6f |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-ca8daa10701047cd986ead9e1edb2d6f2025-08-20T03:41:08ZengWileyAdvanced Science2198-38442025-08-011229n/an/a10.1002/advs.202502740Fast pH‐Driven Solubilization Method of Realgar (As4S4) to Reduce the Toxicity of Arsenic [As(III)] for Medicinal PurposesBojana Lucic0Douglas Santana Franciscato1Helton Pereira Nogueira2Lara Gallucci3Alceu Totti Silveira Junior4Asmaa Mohamed Ismail5Millie Robinson6Teresa Dallinger7Claudia Gutfleisch8Jochen Kurz9Maytê Toledo10Jessica Dias da Silva Ferraz11Mohammad Tarek12Danilo Dias13Ricardo Sobhie Diaz14Mahmoud ElHefnawi15Mattia Forcato16Hugo P Monteiro17Marina Lusic18Iart Luca Shytaj19Andrea Savarino20Department of Infectious Diseases Integrative Virology Heidelberg University 69120 Heidelberg GermanyInstitute of Chemistry University of São Paulo São Paulo 05508‐220 BrazilInstitute of Chemistry University of São Paulo São Paulo 05508‐220 BrazilSchool of Cellular and Molecular Medicine University of Bristol Bristol BS8 1TD UKInstitute of Chemistry University of São Paulo São Paulo 05508‐220 BrazilSpectroscopy Department National Research Centre 33 El Bohouth Street Dokki Giza 12622 EgyptSchool of Cellular and Molecular Medicine University of Bristol Bristol BS8 1TD UKDepartment of Infectious Diseases Integrative Virology Heidelberg University 69120 Heidelberg GermanyCenter for Infectious Diseases Medical Microbiology und Hygiene University Hospital Heidelberg 69120 Heidelberg GermanyCenter for Infectious Diseases Medical Microbiology und Hygiene University Hospital Heidelberg 69120 Heidelberg GermanyDepartment of Biochemistry Center for Cellular and Molecular Therapy Federal University of São Paulo São Paulo 04021‐001 BrazilInfectious Diseases Department Federal University of São Paulo São Paulo 04021‐001 BrazilClinical Hematology Department Armed Forces College of Medicine (AFCM) Cairo Governatorate Heliopolis 11774 EgyptInfectious Diseases Department Federal University of São Paulo São Paulo 04021‐001 BrazilInfectious Diseases Department Federal University of São Paulo São Paulo 04021‐001 BrazilInformatics and Systems Department National Research Centre 33 El Bohouth Street, Dokki Giza 12622 EgyptDepartment of Molecular Medicine University of Padova Padova 35122 ItalyDepartment of Biochemistry Center for Cellular and Molecular Therapy Federal University of São Paulo São Paulo 04021‐001 BrazilDepartment of Infectious Diseases Integrative Virology Heidelberg University 69120 Heidelberg GermanySchool of Cellular and Molecular Medicine University of Bristol Bristol BS8 1TD UKDepartment of Infectious Diseases Italian Institute of Health Rome 00161 ItalyAbstract 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.https://doi.org/10.1002/advs.202502740Acute Promyelocytic LeukemiaArsenic TrioxideHIVPMLRealgar |
| spellingShingle | Bojana Lucic Douglas Santana Franciscato Helton Pereira Nogueira Lara Gallucci Alceu Totti Silveira Junior Asmaa Mohamed Ismail Millie Robinson Teresa Dallinger Claudia Gutfleisch Jochen Kurz Maytê Toledo Jessica Dias da Silva Ferraz Mohammad Tarek Danilo Dias Ricardo Sobhie Diaz Mahmoud ElHefnawi Mattia Forcato Hugo P Monteiro Marina Lusic Iart Luca Shytaj Andrea Savarino Fast pH‐Driven Solubilization Method of Realgar (As4S4) to Reduce the Toxicity of Arsenic [As(III)] for Medicinal Purposes Advanced Science Acute Promyelocytic Leukemia Arsenic Trioxide HIV PML Realgar |
| title | Fast pH‐Driven Solubilization Method of Realgar (As4S4) to Reduce the Toxicity of Arsenic [As(III)] for Medicinal Purposes |
| title_full | Fast pH‐Driven Solubilization Method of Realgar (As4S4) to Reduce the Toxicity of Arsenic [As(III)] for Medicinal Purposes |
| title_fullStr | Fast pH‐Driven Solubilization Method of Realgar (As4S4) to Reduce the Toxicity of Arsenic [As(III)] for Medicinal Purposes |
| title_full_unstemmed | Fast pH‐Driven Solubilization Method of Realgar (As4S4) to Reduce the Toxicity of Arsenic [As(III)] for Medicinal Purposes |
| title_short | Fast pH‐Driven Solubilization Method of Realgar (As4S4) to Reduce the Toxicity of Arsenic [As(III)] for Medicinal Purposes |
| title_sort | fast ph driven solubilization method of realgar as4s4 to reduce the toxicity of arsenic as iii for medicinal purposes |
| topic | Acute Promyelocytic Leukemia Arsenic Trioxide HIV PML Realgar |
| url | https://doi.org/10.1002/advs.202502740 |
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