Mutation Status and Glucose Availability Affect the Response to Mitochondria-Targeted Quercetin Derivative in Breast Cancer Cells

Simple Summary In the present study, we synthesized and characterized the physicochemical properties and anticancer activity of three non-polar, mitochondria-targeted derivatives of quercetin. Since all hydroxy groups are blocked, the compounds are not able to break the peroxidation of lipids; thus, high lipophilicity and strong interactions with lipid bilayers are principal factors affecting the bioactivity of the three derivatives. We focused on novel aspects of the bio-applications of mito-quercetin, which were never studied before. The novelty is based on the following: (a) cellular model—six different breast cancer cell lines (different mutation and receptor status); (b) different mito-quercetin derivatives with blocked “redox-active” groups that allow for a comparative analysis of previously published data on quercetin derivatives with free catechol moiety; (c) different experimental settings with high and low glucose concentrations to measure glucose availability and energetic stress; (d) the analysis of prosenescent and senolytic activity of mito-quercetin. For the first time, we show the importance of the genetic background, which, in this case, is the mutation status of breast cancer cells for the activity of quercetin derivatives, and we show that mito-quercetin is more effective than quercetin in the elimination of breast cancer cells with different mutation status. 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.