Highly malignant triple-negative breast cancer (TNBC) cells rely mostly on glycolysis to maintain cellular homeostasis; however, mitochondria are still required for migration and metastasis. Taking advantage of the metabolic flexibility of TNBC MDA-MB-231 cells to generate subpopulations with glycolytic or oxidative phenotypes, we screened phenolic compounds containing an ortho-carbonyl group with mitochondrial activity and identified a bromoalkyl-ester of hydroquinone named FR58P1a, as a mitochondrial metabolism-affecting compound that uncouples OXPHOS through a protonophoric mechanism. In contrast to well-known protonophore uncoupler FCCP, FR58P1a does not depolarize the plasma membrane and its effect on the mitochondrial membrane potential and bioenergetics is moderate suggesting a mild uncoupling of OXPHOS. FR58P1a activates AMPK in a Sirt1-dependent fashion. Although the activation of Sirt1/AMPK axis by FR58P1a has a cyto-protective role, selectively inhibits fibronectin-dependent adhesion and migration in TNBC cells but not in non-tumoral MCF10A cells by decreasing β1-integrin at the cell surface. Prolonged exposure to FR58P1a triggers a metabolic reprograming in TNBC cells characterized by down-regulation of OXPHOS-related genes that promote cell survival but comprise their ability to migrate. Taken together, our results show that TNBC cell migration is susceptible to mitochondrial alterations induced by small molecules as FR58P1a, which may have therapeutic implications.

No abstract

Artículo de publicación ISIThe effect of carbonyl groups in the ortho position with respect to a hydroxyl group on the electrochemical oxidation of hydroquinones in acetonitrile is studied. The electrochemical response of hydroquinone on a glassy carbon electrode in 0.1 M tetrabutylammonium perchlorate was investigated in detail by voltammetry and coulometry. From these experiments, the oxidation potential was shifted to more positive values with respect to hydroquinone due to the presence of electron withdrawing groups bonded to the aromatic ring. For all compounds a diffusional behavior was observed, and the diffusion coefficient (D) of substituted hydroquinones was calculated showing higher values than found for unsubstituted hydroquinone. Theoretical calculations were carried out to gain insights into the intramolecular hydrogen bond present in these molecules affecting their electrochemical behavior. Relevant theoretical data are optimized geometrical parameters, HOMO energy, condensed radical Fukui functions (f(o)), natural charges, Wiberg bond orders (WBO), stabilization energies caused by electron transfer, and hyperconjugation stabilization energies from the NBO analysis. In most cases, the calculations show good agreement with experimental H-1-NMR data and support the electrochemical results.FONDECYT, DICYT USACH, AC

The rational design of quinones with specific redox properties is an issue of great interest because of their applications in pharmaceutical and material sciences. In this work, the electrochemical behavior of a series of four p-quinones was studied experimentally and theoretically. The first and second one-electron reduction potentials of the quinones were determined using cyclic voltammetry and correlated with those calculated by density functional theory (DFT) using three different functionals, BHandHLYP, M06-2x and PBE0. The differences among the experimental reduction potentials were explained in terms of structural effects on the stabilities of the formed species. DFT calculations accurately reproduced the first one-electron experimental reduction potentials with R2 higher than 0.94. The BHandHLYP functional presented the best fit to the experimental values (R2 = 0.957), followed by M06-2x (R2 = 0.947) and PBE0 (R2 = 0.942).