Selisistat, a SIRT1 inhibitor, enhances paclitaxel activity in luminal and triple-negative breast cancer: in silico, in vitro, and in vivo studies
Sirtuins (SIRTs) are NAD+-dependent histone deacetylases, which play a key role in cancer progression; however, their prognostic values in breast cancer (BC) remain a subject of debate and controversy. Accumulative evidence suggests that each sirtuin possesses individual character, implicating its r...
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Taylor & Francis Group
2025-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2025.2458554 |
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| author | Anna Wawruszak Jarogniew Luszczki Damian Bartuzi Joanna Kalafut Estera Okon Arkadiusz Czerwonka Andrzej Stepulak |
| author_facet | Anna Wawruszak Jarogniew Luszczki Damian Bartuzi Joanna Kalafut Estera Okon Arkadiusz Czerwonka Andrzej Stepulak |
| author_sort | Anna Wawruszak |
| collection | DOAJ |
| description | Sirtuins (SIRTs) are NAD+-dependent histone deacetylases, which play a key role in cancer progression; however, their prognostic values in breast cancer (BC) remain a subject of debate and controversy. Accumulative evidence suggests that each sirtuin possesses individual character, implicating its role in the regulation of multifaceted biological functions leading to BC initiation, progression and metastasis. Selisistat (EX527) is a potent, cell permeable, highly selective SIRT1 inhibitor. In the study, the tumour-suppressive effects of the SIRT1 inhibitor EX527 (selisistat) alone and in combination with paclitaxel (PAX) in different breast cancer cell lines and zebrafish xenograft models were investigated. The type of pharmacological drug-drug interaction between EX527 and PAX was determined using the isobolographic method. EX527 and PAX used individually inhibited proliferation, induced apoptosis and caused cell cycle arrest in G1 and subG1/G2 phases. Interestingly, the combination of these compounds used in the 1:1 dose-ratio augmented all these effects (IC50add 29.52 ± 3.29 − 38.45 ± 5.26). The co-treatment of EX527 with PAX generated desirable additive drug-drug interaction. The simultaneous application of EX527 and PAX induced a stronger inhibition of tumour growth compared to individual treatments in zebrafish xenografts. In silico analysis revealed a protein-protein interaction pathway (SIRT1-AKT-S1PR1-GNAI1/GNAO1-Tubulin) connecting molecular targets of both ligands. To summarise, the combination of EX527 and PAX more effectively impairs breast cancer cell growth compared to individual treatments. However, further investigations are required to clarify the specific targets and molecular mechanisms underlying the activity of EX527:PAX in other preclinical models. |
| format | Article |
| id | doaj-art-e397db362cfb4bc7852d8583e38d89b2 |
| institution | DOAJ |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-e397db362cfb4bc7852d8583e38d89b22025-08-20T03:12:19ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742025-12-0140110.1080/14756366.2025.2458554Selisistat, a SIRT1 inhibitor, enhances paclitaxel activity in luminal and triple-negative breast cancer: in silico, in vitro, and in vivo studiesAnna Wawruszak0Jarogniew Luszczki1Damian Bartuzi2Joanna Kalafut3Estera Okon4Arkadiusz Czerwonka5Andrzej Stepulak6Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, PolandDepartment of Occupational Medicine, Medical University of Lublin, Lublin, PolandDepartment of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modelling Laboratory, Medical University of Lublin, Lublin, PolandDepartment of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, PolandDepartment of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, PolandDepartment of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, PolandDepartment of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, PolandSirtuins (SIRTs) are NAD+-dependent histone deacetylases, which play a key role in cancer progression; however, their prognostic values in breast cancer (BC) remain a subject of debate and controversy. Accumulative evidence suggests that each sirtuin possesses individual character, implicating its role in the regulation of multifaceted biological functions leading to BC initiation, progression and metastasis. Selisistat (EX527) is a potent, cell permeable, highly selective SIRT1 inhibitor. In the study, the tumour-suppressive effects of the SIRT1 inhibitor EX527 (selisistat) alone and in combination with paclitaxel (PAX) in different breast cancer cell lines and zebrafish xenograft models were investigated. The type of pharmacological drug-drug interaction between EX527 and PAX was determined using the isobolographic method. EX527 and PAX used individually inhibited proliferation, induced apoptosis and caused cell cycle arrest in G1 and subG1/G2 phases. Interestingly, the combination of these compounds used in the 1:1 dose-ratio augmented all these effects (IC50add 29.52 ± 3.29 − 38.45 ± 5.26). The co-treatment of EX527 with PAX generated desirable additive drug-drug interaction. The simultaneous application of EX527 and PAX induced a stronger inhibition of tumour growth compared to individual treatments in zebrafish xenografts. In silico analysis revealed a protein-protein interaction pathway (SIRT1-AKT-S1PR1-GNAI1/GNAO1-Tubulin) connecting molecular targets of both ligands. To summarise, the combination of EX527 and PAX more effectively impairs breast cancer cell growth compared to individual treatments. However, further investigations are required to clarify the specific targets and molecular mechanisms underlying the activity of EX527:PAX in other preclinical models.https://www.tandfonline.com/doi/10.1080/14756366.2025.2458554Breast cancerpaclitaxelselisistatsirtuin inhibitorhistone deacetylase inhibitor |
| spellingShingle | Anna Wawruszak Jarogniew Luszczki Damian Bartuzi Joanna Kalafut Estera Okon Arkadiusz Czerwonka Andrzej Stepulak Selisistat, a SIRT1 inhibitor, enhances paclitaxel activity in luminal and triple-negative breast cancer: in silico, in vitro, and in vivo studies Journal of Enzyme Inhibition and Medicinal Chemistry Breast cancer paclitaxel selisistat sirtuin inhibitor histone deacetylase inhibitor |
| title | Selisistat, a SIRT1 inhibitor, enhances paclitaxel activity in luminal and triple-negative breast cancer: in silico, in vitro, and in vivo studies |
| title_full | Selisistat, a SIRT1 inhibitor, enhances paclitaxel activity in luminal and triple-negative breast cancer: in silico, in vitro, and in vivo studies |
| title_fullStr | Selisistat, a SIRT1 inhibitor, enhances paclitaxel activity in luminal and triple-negative breast cancer: in silico, in vitro, and in vivo studies |
| title_full_unstemmed | Selisistat, a SIRT1 inhibitor, enhances paclitaxel activity in luminal and triple-negative breast cancer: in silico, in vitro, and in vivo studies |
| title_short | Selisistat, a SIRT1 inhibitor, enhances paclitaxel activity in luminal and triple-negative breast cancer: in silico, in vitro, and in vivo studies |
| title_sort | selisistat a sirt1 inhibitor enhances paclitaxel activity in luminal and triple negative breast cancer in silico in vitro and in vivo studies |
| topic | Breast cancer paclitaxel selisistat sirtuin inhibitor histone deacetylase inhibitor |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2025.2458554 |
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