Novel dual action chimera doxorubizen demonstrates superior efficacy to doxorubicin in acute leukemia
Abstract Modifying existing drugs to enhance their activity and reduce toxicity is a major focus of drug development. We developed a novel class of dual-action chimeric molecules for cancer therapy, linking known drugs to a DNA-methylating monomethyl triazene moiety (azene) via nucleophilic substitu...
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Nature Portfolio
2025-03-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-94373-8 |
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| author | Dipak Walunj Katarina Egarmina Adi Zipin-Roitman Siva Sai Naga Anurag Muddineni Iryna Tkachenko Pousali Mitra Dror Tobi Andrii Bazylevich Ofer Shpilberg Michael Milyavsky Oshrat Hershkovitz-Rokah Gary Gellerman |
| author_facet | Dipak Walunj Katarina Egarmina Adi Zipin-Roitman Siva Sai Naga Anurag Muddineni Iryna Tkachenko Pousali Mitra Dror Tobi Andrii Bazylevich Ofer Shpilberg Michael Milyavsky Oshrat Hershkovitz-Rokah Gary Gellerman |
| author_sort | Dipak Walunj |
| collection | DOAJ |
| description | Abstract Modifying existing drugs to enhance their activity and reduce toxicity is a major focus of drug development. We developed a novel class of dual-action chimeric molecules for cancer therapy, linking known drugs to a DNA-methylating monomethyl triazene moiety (azene) via nucleophilic substitution. In-vitro screening of these chimeras on various leukemia cell lines identified a potent chimera, doxorubizen, a sequel of the known DNA intercalator and topoisomerase 2 (Topo-II) inhibitor doxorubicin (Dox) and azene. Molecular docking and dynamic simulations showed doxorubizen as a more potent Topo-II inhibitor than Dox as it binds to major grooves in DNA. Moreover, the monomethyl triazene portion is positioned favorably through tetracene core intercalation, potentially facilitating methylation at nearby guanine bases. Doxorubizen demonstrated significantly higher cytotoxicity, mitochondrial depolarization, DNA intercalation, and cell death than Dox. A Topo-II activity assay confirmed potent enzyme inhibition by doxorubizen. The mechanism of action of doxorubizen involves the inhibition of DNA repair in proximity to double-strand breaks by guanine methylation, enhanced mitochondrial depolarization, and increased apoptosis. Furthermore, in an acute leukemia xenograft model, doxorubizen significantly reduced the leukemia burden compared to Dox while preserving body weight and liver function. This work underscores the therapeutic potential of doxorubizen in leukemia treatment. |
| format | Article |
| id | doaj-art-63718f8cba4e490e8d765d046e98ecc8 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-63718f8cba4e490e8d765d046e98ecc82025-08-20T02:10:23ZengNature PortfolioScientific Reports2045-23222025-03-0115111710.1038/s41598-025-94373-8Novel dual action chimera doxorubizen demonstrates superior efficacy to doxorubicin in acute leukemiaDipak Walunj0Katarina Egarmina1Adi Zipin-Roitman2Siva Sai Naga Anurag Muddineni3Iryna Tkachenko4Pousali Mitra5Dror Tobi6Andrii Bazylevich7Ofer Shpilberg8Michael Milyavsky9Oshrat Hershkovitz-Rokah10Gary Gellerman11Department of Chemical Sciences, Ariel UniversityDepartment of Molecular Biology, Ariel UniversityDepartment of Pathology, Faculty of Medical & Health Sciences, Tel-Aviv UniversityDepartment of Chemical Sciences, Ariel UniversityDepartment of Chemical Sciences, Ariel UniversityDepartment of Chemical Sciences, Ariel UniversityDepartment of Molecular Biology, Ariel UniversityDepartment of Chemical Sciences, Ariel UniversityAdelson School of Medicine, Ariel UniversityDepartment of Pathology, Faculty of Medical & Health Sciences, Tel-Aviv UniversityDepartment of Molecular Biology, Ariel UniversityDepartment of Chemical Sciences, Ariel UniversityAbstract Modifying existing drugs to enhance their activity and reduce toxicity is a major focus of drug development. We developed a novel class of dual-action chimeric molecules for cancer therapy, linking known drugs to a DNA-methylating monomethyl triazene moiety (azene) via nucleophilic substitution. In-vitro screening of these chimeras on various leukemia cell lines identified a potent chimera, doxorubizen, a sequel of the known DNA intercalator and topoisomerase 2 (Topo-II) inhibitor doxorubicin (Dox) and azene. Molecular docking and dynamic simulations showed doxorubizen as a more potent Topo-II inhibitor than Dox as it binds to major grooves in DNA. Moreover, the monomethyl triazene portion is positioned favorably through tetracene core intercalation, potentially facilitating methylation at nearby guanine bases. Doxorubizen demonstrated significantly higher cytotoxicity, mitochondrial depolarization, DNA intercalation, and cell death than Dox. A Topo-II activity assay confirmed potent enzyme inhibition by doxorubizen. The mechanism of action of doxorubizen involves the inhibition of DNA repair in proximity to double-strand breaks by guanine methylation, enhanced mitochondrial depolarization, and increased apoptosis. Furthermore, in an acute leukemia xenograft model, doxorubizen significantly reduced the leukemia burden compared to Dox while preserving body weight and liver function. This work underscores the therapeutic potential of doxorubizen in leukemia treatment.https://doi.org/10.1038/s41598-025-94373-8Anticancer drugDNA intercalationDNA double-strand breaksMolecular |
| spellingShingle | Dipak Walunj Katarina Egarmina Adi Zipin-Roitman Siva Sai Naga Anurag Muddineni Iryna Tkachenko Pousali Mitra Dror Tobi Andrii Bazylevich Ofer Shpilberg Michael Milyavsky Oshrat Hershkovitz-Rokah Gary Gellerman Novel dual action chimera doxorubizen demonstrates superior efficacy to doxorubicin in acute leukemia Scientific Reports Anticancer drug DNA intercalation DNA double-strand breaks Molecular |
| title | Novel dual action chimera doxorubizen demonstrates superior efficacy to doxorubicin in acute leukemia |
| title_full | Novel dual action chimera doxorubizen demonstrates superior efficacy to doxorubicin in acute leukemia |
| title_fullStr | Novel dual action chimera doxorubizen demonstrates superior efficacy to doxorubicin in acute leukemia |
| title_full_unstemmed | Novel dual action chimera doxorubizen demonstrates superior efficacy to doxorubicin in acute leukemia |
| title_short | Novel dual action chimera doxorubizen demonstrates superior efficacy to doxorubicin in acute leukemia |
| title_sort | novel dual action chimera doxorubizen demonstrates superior efficacy to doxorubicin in acute leukemia |
| topic | Anticancer drug DNA intercalation DNA double-strand breaks Molecular |
| url | https://doi.org/10.1038/s41598-025-94373-8 |
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