Abstract
BackgroundTargeting negatively charged mitochondria is often achieved using triphenylphosphonium (TPP) cations. These cationic vehicles may possess biological activity, and a docking study indicates that TPP-moieties may act as modulators of signaling through the estrogen receptor α (ERα). Moreover, in vivo and in vitro experiments revealed the estrogen-like effects of TPP-based compounds. Here, we tested the hypothesis that TPP-based compounds regulate the activity of ERα.MethodsWe used ERa-positive and ERα-negative human breast adenocarcinoma cell lines (MCF-7 and MDA-MB-231, respectively). Cell proliferation was measured using a resazurin cell growth assay and a real-time cell analyzer assay. Cell cycle progression was analyzed using flow cytometry. Real-time PCR was used to assess mRNA expression of endogenous estrogen-responsive genes. Luciferase activity was measured to evaluate transcription driven by estrogen-responsive promoters in cells transfected with an estrogen response element (ERE)3-luciferase expression vector.ResultsThe TPP-based molecules SkQ1 and C12TPP, as well as the rhodamine-based SkQR1, did not increase the proliferation or alter the cell cycle progression of MCF-7 cells. In contrast, 17β estradiol increased the proliferation of MCF-7 cells and the proportion of cells in the S/G2/M-phases of the cell cycle. TPP-based compounds did not affect the induction of transcription of an ERE-luciferase expression vector in vitro, and SkQ1 did not alter the levels of expression of estrogen-dependent genes encoding GREB1, TFF1, COX6, and IGFBP4.ConclusionTPP-based compounds do not possess properties typical of ERα agonists.
Highlights
Mitochondria are important target for drug development (Zielonka et al, 2017)
ER-positive MCF-7 cells were incubated for 48 h with the test compounds with or without fulvestrant, and cell growth was measured using the resazurin test
20 nM SkQ1, 0.2 nM C12TPP, 20 nM C12TPP and 20 nM SkQR1 increased resazurin fluorescence by approximately 10% compared with untreated cells (Fig. 2)
Summary
Mitochondria are important target for drug development (Zielonka et al, 2017). Mitochondria-targeted molecules include drug candidates, intracellular probes and sensors (Zinovkin & Zamyatnin, 2019). Mitochondria-targeted triphenylphosphonium-based compounds do not affect estrogen receptor α. Indirect evidence supports the possibility that the TPP-based antioxidants MitoQ and SkQ1 act through estrogen-like action as follows:. The mitochondria of MCF-7 and endothelial cells contain functional high-affinity ERs (Pedram et al, 2006) Activation of these receptors by E2 inhibits UV radiation-induced cytochrome C release, decreased mitochondrial membrane potential, and apoptosis via the formation of mitochondrial reactive oxygen species (mROS) (Pedram et al, 2006). TPP-based mitochondria-targeted compounds may possess estrogen-like activities, and it is critically important to investigate this possibility. The mitochondria-targeted antioxidant SkQR1, which lacks the TPP moiety, served as a negative control
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