Dane do artykułu "Mutation Status and Glucose Availability Affect the Response to Mitochondria-Targeted Quercetin Derivative in Breast Cancer Cells"
Date
2023-11-28
Journal Title
Journal ISSN
Volume Title
Depositor
Publisher
Cancers (Basel) MDPI
Abstract
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.
Description
S1. Synthesis of mitochondrial derivatives: S1.1. General information, S1.2. Synthesis and identification of mitQ7, S1.3. Synthesis and identification of mitQ3, S1.4. Synthesis and identification of mitQ5. S2. NMR spectral data. S3. Kinetic measurements for quercetin. SCHEMES: Scheme S1. Synthetic pathway for mitQ7, Scheme S2. Synthetic pathway for mitQ3, Scheme S3. Synthetic pathway for mitQ5. TABLES: Table S1. Kinetic parameters for autoxidation of methyl linoleate DMPC liposomes in the presence of 1 µM quercetin at pH range from 4 to 9. Table S2. Thermodynamic parameters determined from DSC experiments. FIGURES: Figures S1–S25. The 1H and 13C NMR spectral data for quercetin derivatives. Figure S26. Plots of oxygen uptake during peroxidation inhibited by quercetin. Figure S27. ADME parameters calculated for quercetin. Figure S28. ADME parameters calculated for mitQ3. Figure S29. ADME parameters calculated for mitQ5. Figure S30. ADME parameters calculated for mitQ7. Figure S31. The effects of quercetin (Q) and mito-quercetin derivatives (mitQ3, 5, and 7) on metabolic activity of six breast cancer cell lines. Figure S32. Mitochondria-related gene mutation status and correlation analysis between the metabolic activity and the number of gene mutations in genes involved in mitochondrial functions in breast cancer cells. Figure S33. Kinase gene mutation status and correlation analysis between the metabolic activity and the number of kinase gene mutations in breast cancer cells. Figure S34. MitQ7-mediated changes in the phases of cell cycle in breast cancer cells. Figure S35. MitQ7-induced apoptosis in breast cancer cells. Figure S36. MitQ7-mediated changes in intracellular pH in breast cancer cells. Figure S37. MitQ7-mediated senolytic activity in doxorubicin-induced senescent breast cancer cells. Figure S38. MitQ7-mediated changes in mitochondrial transmembrane potential in doxorubicin-induced senescent breast cancer cells. Supplementary Material 2: Kobas_raw_data. Supplementary Material 3: Table S3. Intersection of gene mutations set in six breast cancer cell lines used in this study and presented in Figure 3 with the use of Kobas standalone software. Table S4. Intersection of gene mutations set linked with mitochondrial functions in six breast cancer cell lines used in this study and presented in Figure S32 with the use of Kobas standalone software. Table S5. Intersection of gene mutations set linked with kinases pathways in six breast cancer cell lines used in this study and presented in Figure S33 with the use of Kobas standalone software.
Exel file with dataset used to prepare the charts
Keywords
mito-quercetin, breast cancer, doxorubicin-induced senescence
Related publications
Przybylski P, Lewińska A, Rzeszutek I, Błoniarz D, Moskal A, Betlej G, Deręgowska A, Cybularczyk-Cecotka M, Szmatoła T, Litwinienko G, Wnuk M. Mutation Status and Glucose Availability Affect the Response to Mitochondria-Targeted Quercetin Derivative in Breast Cancer Cells. Cancers (Basel). 2023 Nov 28;15(23):5614
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Attribution 4.0 International
Research funding institutions
This work was supported by the National Science Centre (NCN, Poland) grant OPUS 22 No. 2021/43/B/NZ7/02129 for M.W. The first step of synthesis of quercetin derivatives (protection of catechol groups with O-diphenylmethane) was carried out as a part of another project in which the physico-chemical properties of derivatives with free hydroxy groups were tested (grant OPUS 16 No. 2018/31/B/ST4/02354 received from NCN by G.L.).
Type
processed dataset