Abacavir enhances the efficacy of doxorubicin via inhibition of histone demethylase KDM5B in breast cancer
Abstract KDM5B, a lysine-specific histone demethylase, is widely upregulated in breast cancer. The current study investigated the role of KDM5B in breast cancer and explored the repurposing potential of the antiviral drug abacavir (ABC). The cytotoxic effects and the effect of ABC sensitization on d...
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Nature Portfolio
2025-08-01
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| Online Access: | https://doi.org/10.1038/s41598-025-13845-z |
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| author | Anmi Jose Pallavi Kulkarni Naveena AN Kumar Nawaz Usman Gabriel Sunil Rodrigues Gautham G. Shenoy Rama Rao Damerla Murali Munisamy Bharti Bisht Sooryanarayana Varambally Manash K. Paul Neha Arya Praveen PN Rao Mahadev Rao |
| author_facet | Anmi Jose Pallavi Kulkarni Naveena AN Kumar Nawaz Usman Gabriel Sunil Rodrigues Gautham G. Shenoy Rama Rao Damerla Murali Munisamy Bharti Bisht Sooryanarayana Varambally Manash K. Paul Neha Arya Praveen PN Rao Mahadev Rao |
| author_sort | Anmi Jose |
| collection | DOAJ |
| description | Abstract KDM5B, a lysine-specific histone demethylase, is widely upregulated in breast cancer. The current study investigated the role of KDM5B in breast cancer and explored the repurposing potential of the antiviral drug abacavir (ABC). The cytotoxic effects and the effect of ABC sensitization on doxorubicin (DOX) efficacy were evaluated using 2-D and 3-D cell culture models. KDM5B expression was elevated in breast cancer tissues compared to normal breast tissues. In vitro studies demonstrated that ABC treatment reduced KDM5B expression in breast cancer cells and increased their sensitivity towards DOX. ABC induced late apoptosis and S-phase arrest, while the ABC + DOX combination led to S/G2 phase arrest, late apoptosis, and cell death. Data generated from patient-derived breast tumoroids corroborated the 2-D cell culture-based findings. Additionally, molecular docking studies indicated that the active drug metabolite carbovir triphosphate (CBV-TP) could interact with the DNA polymerase β-DNA complex, suggesting its potential mechanism to be incorporated into the DNA synthesis cycle, leading to cell cycle arrest in tumor cells. Our findings highlight the repurposing potential of ABC to target KDM5B in breast cancer. This approach enhanced the efficacy of DOX, which could allow further dose reduction and reduced side effects, offering a promising therapeutic strategy. |
| format | Article |
| id | doaj-art-a5156313bfc54ac6bfccacc53a0f6b9e |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-a5156313bfc54ac6bfccacc53a0f6b9e2025-08-20T03:42:49ZengNature PortfolioScientific Reports2045-23222025-08-0115111610.1038/s41598-025-13845-zAbacavir enhances the efficacy of doxorubicin via inhibition of histone demethylase KDM5B in breast cancerAnmi Jose0Pallavi Kulkarni1Naveena AN Kumar2Nawaz Usman3Gabriel Sunil Rodrigues4Gautham G. Shenoy5Rama Rao Damerla6Murali Munisamy7Bharti Bisht8Sooryanarayana Varambally9Manash K. Paul10Neha Arya11Praveen PN Rao12Mahadev Rao13Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher EducationDepartment of Biochemistry, All India Institute of Medical Sciences BhopalDepartment of Surgical Oncology, Manipal Comprehensive Cancer Care Centre, Kasturba Medical College, Manipal Academy of Higher EducationDepartment of Surgical Oncology, Manipal Comprehensive Cancer Care Centre, Kasturba Medical College, Manipal Academy of Higher EducationDepartment of General Surgery, Kasturba Medical College, Manipal Academy of Higher EducationDepartment of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher EducationDepartment of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher EducationDepartment of Translational Medicine, All India Institute of Medical Sciences BhopalDepartment of Microbiology, Kasturba Medical College, Manipal Academy of Higher EducationDepartment of Pathology, University of Alabama at BirminghamDepartment of Radiation Biology and Toxicology, Manipal School of Life Sciences, Manipal Academy of Higher EducationDepartment of Translational Medicine, All India Institute of Medical Sciences BhopalSchool of Pharmacy, Health Sciences Campus, University of WaterlooDepartment of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher EducationAbstract KDM5B, a lysine-specific histone demethylase, is widely upregulated in breast cancer. The current study investigated the role of KDM5B in breast cancer and explored the repurposing potential of the antiviral drug abacavir (ABC). The cytotoxic effects and the effect of ABC sensitization on doxorubicin (DOX) efficacy were evaluated using 2-D and 3-D cell culture models. KDM5B expression was elevated in breast cancer tissues compared to normal breast tissues. In vitro studies demonstrated that ABC treatment reduced KDM5B expression in breast cancer cells and increased their sensitivity towards DOX. ABC induced late apoptosis and S-phase arrest, while the ABC + DOX combination led to S/G2 phase arrest, late apoptosis, and cell death. Data generated from patient-derived breast tumoroids corroborated the 2-D cell culture-based findings. Additionally, molecular docking studies indicated that the active drug metabolite carbovir triphosphate (CBV-TP) could interact with the DNA polymerase β-DNA complex, suggesting its potential mechanism to be incorporated into the DNA synthesis cycle, leading to cell cycle arrest in tumor cells. Our findings highlight the repurposing potential of ABC to target KDM5B in breast cancer. This approach enhanced the efficacy of DOX, which could allow further dose reduction and reduced side effects, offering a promising therapeutic strategy.https://doi.org/10.1038/s41598-025-13845-zBreast cancerCarbovir triphosphateDrug repurposingEpigenetic targetingPrecision medicine |
| spellingShingle | Anmi Jose Pallavi Kulkarni Naveena AN Kumar Nawaz Usman Gabriel Sunil Rodrigues Gautham G. Shenoy Rama Rao Damerla Murali Munisamy Bharti Bisht Sooryanarayana Varambally Manash K. Paul Neha Arya Praveen PN Rao Mahadev Rao Abacavir enhances the efficacy of doxorubicin via inhibition of histone demethylase KDM5B in breast cancer Scientific Reports Breast cancer Carbovir triphosphate Drug repurposing Epigenetic targeting Precision medicine |
| title | Abacavir enhances the efficacy of doxorubicin via inhibition of histone demethylase KDM5B in breast cancer |
| title_full | Abacavir enhances the efficacy of doxorubicin via inhibition of histone demethylase KDM5B in breast cancer |
| title_fullStr | Abacavir enhances the efficacy of doxorubicin via inhibition of histone demethylase KDM5B in breast cancer |
| title_full_unstemmed | Abacavir enhances the efficacy of doxorubicin via inhibition of histone demethylase KDM5B in breast cancer |
| title_short | Abacavir enhances the efficacy of doxorubicin via inhibition of histone demethylase KDM5B in breast cancer |
| title_sort | abacavir enhances the efficacy of doxorubicin via inhibition of histone demethylase kdm5b in breast cancer |
| topic | Breast cancer Carbovir triphosphate Drug repurposing Epigenetic targeting Precision medicine |
| url | https://doi.org/10.1038/s41598-025-13845-z |
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