Molecular Mechanisms of Nemorosone-Induced Ferroptosis in Cancer Cells

Abstract

Ferroptosis is an iron-dependent cell that is death-driven by the excessive peroxidation of the polyunsaturated fatty acids (PUFAs) of membranes. A growing body of evidence suggests the induction of ferroptosis as a cutting-edge strategy in cancer treatment research. Despite the essential role of mitochondria in cellular metabolism, bioenergetics, and cell death, their function in ferroptosis is still poorly understood. Recently, mitochondria were elucidated as an important component in cysteine-deprivation-induced (CDI) ferroptosis, which provides novel targets in the search for new ferroptosis-inducing compounds (FINs). Here, we identified the natural mitochondrial uncoupler nemorosone as a ferroptosis inducer in cancer cells. Interestingly, nemorosone triggers ferroptosis by a double-edged mechanism. In addition to decreasing the glutathione (GSH) levels by blocking the System xc cystine/glutamate antiporter (SLC7A11), nemorosone increases the intracellular labile Fe2+ pool via heme oxygenase-1 (HMOX1) induction. Interestingly, a structural variant of nemorosone (O-methylated nemorosone), having lost the capacity to uncouple mitochondrial respiration, does not trigger cell death anymore, suggesting that the mitochondrial bioenergetic disruption via mitochondrial uncoupling is necessary for nemorosone-induced ferroptosis. Our results open novel opportunities for cancer cell killing by mitochondrial uncoupling-induced ferroptosis.

Cartilage Destruction by Hemophilic Arthropathy Can Be Prevented by Inhibition of the Ferroptosis Pathway in Human Chondrocytes

“…The Alamar Blue assay (Thermo Fisher Scientific; Waltham, MA, USA) assessed cell metabolism by detecting fluorescence from viable cells [30]. Chondrocytes (5000/well) were treated with varying concentrations of lysed and non-lysed erythrocytes, IL-1ß, TNFα, ferric citrate, and ML-162 in 48-well plates.…”

“…Human chondrocytes in 96-well plates were treated with ferroptosis inducer ML-162 (5 µM) [29], inhibitors Fer-1 (1 µM) [31][32][33], DFO (20 µM) [30,34], aTOH (20 µM) [35][36][37], apoptosis inhibitor zVAD-fmk (20 µM) [31,38], and necroptosis inhibitor Nec-1 (20 µM) [39] 30 min before erythrocyte exposure. Post-treatment, cells were stained with Sytox green (2 µM) for fluorescence quantification via a Tecan plate reader.…”