Mutation Status and Glucose Availability Affect the Response to Mitochondria-Targeted Quercetin Derivative in Breast Cancer Cells
Mitochondria, the main cellular power stations, are important modulators of redox-sensitive signaling pathways that may determine cell survival and cell death decisions. As mitochondrial function is essential for tumorigenesis and cancer progression, mitochondrial targeting has been proposed as an a...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/23/5614 |
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| author | Paweł Przybylski Anna Lewińska Iwona Rzeszutek Dominika Błoniarz Aleksandra Moskal Gabriela Betlej Anna Deręgowska Martyna Cybularczyk-Cecotka Tomasz Szmatoła Grzegorz Litwinienko Maciej Wnuk |
| author_facet | Paweł Przybylski Anna Lewińska Iwona Rzeszutek Dominika Błoniarz Aleksandra Moskal Gabriela Betlej Anna Deręgowska Martyna Cybularczyk-Cecotka Tomasz Szmatoła Grzegorz Litwinienko Maciej Wnuk |
| author_sort | Paweł Przybylski |
| collection | DOAJ |
| description | Mitochondria, the main cellular power stations, are important modulators of redox-sensitive signaling pathways that may determine cell survival and cell death decisions. As mitochondrial function is essential for tumorigenesis and cancer progression, mitochondrial targeting has been proposed as an attractive anticancer strategy. In the present study, three mitochondria-targeted quercetin derivatives (mitQ3, 5, and 7) were synthesized and tested against six breast cancer cell lines with different mutation and receptor status, namely ER-positive MCF-7, HER2-positive SK-BR-3, and four triple-negative (TNBC) cells, i.e., MDA-MB-231, MDA-MB-468, BT-20, and Hs 578T cells. In general, the mito-quercetin response was modulated by the mutation status. In contrast to unmodified quercetin, 1 µM mitQ7 induced apoptosis in breast cancer cells. In MCF-7 cells, mitQ7-mediated apoptosis was potentiated under glucose-depleted conditions and was accompanied by elevated mitochondrial superoxide production, while AMPK activation-based energetic stress was associated with the alkalization of intracellular milieu and increased levels of NSUN4. Mito-quercetin also eliminated doxorubicin-induced senescent breast cancer cells, which was accompanied by the depolarization of mitochondrial transmembrane potential. Limited glucose availability also sensitized doxorubicin-induced senescent breast cancer cells to apoptosis. In conclusion, we show an increased cytotoxicity of mitochondria-targeted quercetin derivatives compared to unmodified quercetin against breast cancer cells with different mutation status that can be potentiated by modulating glucose availability. |
| first_indexed | 2024-03-09T01:54:14Z |
| format | Article |
| id | doaj.art-d75f28985ccd4688b9a0a9da90cc2ea3 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T01:54:14Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d75f28985ccd4688b9a0a9da90cc2ea32023-12-08T15:12:42ZengMDPI AGCancers2072-66942023-11-011523561410.3390/cancers15235614Mutation Status and Glucose Availability Affect the Response to Mitochondria-Targeted Quercetin Derivative in Breast Cancer CellsPaweł Przybylski0Anna Lewińska1Iwona Rzeszutek2Dominika Błoniarz3Aleksandra Moskal4Gabriela Betlej5Anna Deręgowska6Martyna Cybularczyk-Cecotka7Tomasz Szmatoła8Grzegorz Litwinienko9Maciej Wnuk10Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, PolandInstitute of Biotechnology, College of Natural Sciences, University of Rzeszow, Pigonia 1, 35-310 Rzeszow, PolandInstitute of Biotechnology, College of Natural Sciences, University of Rzeszow, Pigonia 1, 35-310 Rzeszow, PolandInstitute of Biotechnology, College of Natural Sciences, University of Rzeszow, Pigonia 1, 35-310 Rzeszow, PolandInstitute of Biotechnology, College of Natural Sciences, University of Rzeszow, Pigonia 1, 35-310 Rzeszow, PolandInstitute of Biotechnology, College of Natural Sciences, University of Rzeszow, Pigonia 1, 35-310 Rzeszow, PolandInstitute of Biotechnology, College of Natural Sciences, University of Rzeszow, Pigonia 1, 35-310 Rzeszow, PolandFaculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, PolandCenter of Experimental and Innovative Medicine, University of Agriculture in Krakow, al. Mickiewicza 24/28, 30-059 Cracow, PolandFaculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, PolandInstitute of Biotechnology, College of Natural Sciences, University of Rzeszow, Pigonia 1, 35-310 Rzeszow, PolandMitochondria, the main cellular power stations, are important modulators of redox-sensitive signaling pathways that may determine cell survival and cell death decisions. As mitochondrial function is essential for tumorigenesis and cancer progression, mitochondrial targeting has been proposed as an attractive anticancer strategy. In the present study, three mitochondria-targeted quercetin derivatives (mitQ3, 5, and 7) were synthesized and tested against six breast cancer cell lines with different mutation and receptor status, namely ER-positive MCF-7, HER2-positive SK-BR-3, and four triple-negative (TNBC) cells, i.e., MDA-MB-231, MDA-MB-468, BT-20, and Hs 578T cells. In general, the mito-quercetin response was modulated by the mutation status. In contrast to unmodified quercetin, 1 µM mitQ7 induced apoptosis in breast cancer cells. In MCF-7 cells, mitQ7-mediated apoptosis was potentiated under glucose-depleted conditions and was accompanied by elevated mitochondrial superoxide production, while AMPK activation-based energetic stress was associated with the alkalization of intracellular milieu and increased levels of NSUN4. Mito-quercetin also eliminated doxorubicin-induced senescent breast cancer cells, which was accompanied by the depolarization of mitochondrial transmembrane potential. Limited glucose availability also sensitized doxorubicin-induced senescent breast cancer cells to apoptosis. In conclusion, we show an increased cytotoxicity of mitochondria-targeted quercetin derivatives compared to unmodified quercetin against breast cancer cells with different mutation status that can be potentiated by modulating glucose availability.https://www.mdpi.com/2072-6694/15/23/5614mito-quercetinbreast canceroxidative stressAMPKdoxorubicin-induced senescencesenolysis |
| spellingShingle | Paweł Przybylski Anna Lewińska Iwona Rzeszutek Dominika Błoniarz Aleksandra Moskal Gabriela Betlej Anna Deręgowska Martyna Cybularczyk-Cecotka Tomasz Szmatoła Grzegorz Litwinienko Maciej Wnuk Mutation Status and Glucose Availability Affect the Response to Mitochondria-Targeted Quercetin Derivative in Breast Cancer Cells Cancers mito-quercetin breast cancer oxidative stress AMPK doxorubicin-induced senescence senolysis |
| title | Mutation Status and Glucose Availability Affect the Response to Mitochondria-Targeted Quercetin Derivative in Breast Cancer Cells |
| title_full | Mutation Status and Glucose Availability Affect the Response to Mitochondria-Targeted Quercetin Derivative in Breast Cancer Cells |
| title_fullStr | Mutation Status and Glucose Availability Affect the Response to Mitochondria-Targeted Quercetin Derivative in Breast Cancer Cells |
| title_full_unstemmed | Mutation Status and Glucose Availability Affect the Response to Mitochondria-Targeted Quercetin Derivative in Breast Cancer Cells |
| title_short | Mutation Status and Glucose Availability Affect the Response to Mitochondria-Targeted Quercetin Derivative in Breast Cancer Cells |
| title_sort | mutation status and glucose availability affect the response to mitochondria targeted quercetin derivative in breast cancer cells |
| topic | mito-quercetin breast cancer oxidative stress AMPK doxorubicin-induced senescence senolysis |
| url | https://www.mdpi.com/2072-6694/15/23/5614 |
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