Aminic Organoselenium Compounds as Glutathione Peroxidase Mimics and Inhibitors of Ferroptosis.

The synthesis of diarylamine-based organoselenium compounds via the nucleophilic substitution reactions has been described. Symmetrical monoselenides and diselenides were conveniently synthesized by the reduction of their corresponding selenocyanates using sodium borohydride. Selenocyanates were obtained from 2-chloro acetamides by the nucleophilic displacement with potassium selenocyanate.

Thiol starvation triggers melanoma state switching in an ATF4 and NRF2-dependent manner.

The cystine/glutamate antiporter xCT is an important source of cysteine for cancer cells. Once taken up, cystine is reduced to cysteine and serves as a building block for the synthesis of glutathione, which efficiently protects cells from oxidative damage and prevents ferroptosis. As melanomas are particularly exposed to several sources of oxidative stress, we investigated the biological role of cysteine and glutathione supply by xCT in melanoma.

Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation.

Ferroptosis, marked by iron-dependent lipid peroxidation, may present an Achilles heel for the treatment of cancers. Ferroptosis suppressor protein-1 (FSP1), as the second ferroptosis mainstay, efficiently prevents lipid peroxidation via NAD(P)H-dependent reduction of quinones. Because its molecular mechanisms have remained obscure, we studied numerous FSP1 mutations present in cancer or identified by untargeted random mutagenesis.

Sabotaging the breaks: FSEN1 expands the toolbox of FSP1 inhibitors.

The report of heightened lipid peroxidation has shone a spotlight on vulnerabilities within challenging cancers. In this context, FSP1 emerges as a pivotal regulator, actively countering the destructive effects of lipid peroxidation. In a groundbreaking development detailed in the latest issue of Cell Chemical Biology, Hendricks et al.

The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2.

The redox regulator NRF2 becomes activated upon oxidative and electrophilic stress and orchestrates a response program associated with redox regulation, metabolism, tumor therapy resistance, and immune suppression. Here, we describe an unrecognized link between the integrated stress response (ISR) and NRF2 mediated by the ISR effector ATF4. The ISR is commonly activated after starvation or ER stress and plays a central role in tissue homeostasis and cancer plasticity.

Ferroptosis: mechanisms and implications for cancer development and therapy response.

As cancer cells develop resistance to apoptosis, non-apoptotic cell death modalities, such as ferroptosis, have emerged as promising strategies to combat therapy-resistant cancers. Cells that develop resistance to conventional therapies or metastatic cancer cells have been shown to have increased sensitivity to ferroptosis. Therefore, targeting the regulatory elements of ferroptosis in cancer could offer novel therapeutic opportunities.

Molecular characterization of AIFM2/FSP1 inhibition by iFSP1-like molecules.

Ferroptosis is a form of cell death characterized by phospholipid peroxidation, where numerous studies have suggested that the induction of ferroptosis is a therapeutic strategy to target therapy refractory cancer entities. Ferroptosis suppressor protein 1 (FSP1), an NAD(P)H-ubiquinone reductase, is a key determinant of ferroptosis vulnerability, and its pharmacological inhibition was shown to strongly sensitize cancer cells to ferroptosis. A first generation of FSP1 inhibitors, exemplified by the small molecule iFSP1, has been reported; however, the molecular mechanisms underlying inhibition have not been characterized in detail.

Hydropersulfides inhibit lipid peroxidation and ferroptosis by scavenging radicals.

Ferroptosis is a type of cell death caused by radical-driven lipid peroxidation, leading to membrane damage and rupture. Here we show that enzymatically produced sulfane sulfur (S) species, specifically hydropersulfides, scavenge endogenously generated free radicals and, thereby, suppress lipid peroxidation and ferroptosis. By providing sulfur for S biosynthesis, cysteine can support ferroptosis resistance independently of the canonical GPX4 pathway.

GPX4: old lessons, new features.

GPX4 is a selenocysteine-containing protein that plays an essential role in repairing peroxidised phospholipids. Its role in organismal homeostasis has been known for decades, and it has been reported to play a pivotal role in cell survival and mammalian embryonic development. In recent years, GPX4 has been associated with a cell death modality dubbed ferroptosis.

CD8 T cells PUF(A)ing the flames of cancer ferroptotic cell death.

In this issue of Cancer Cell, Liao et al. demonstrate that CD8 T cell-secreted interferon-gamma (IFN-γ) rewires cancer cell lipid metabolism via the enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4). ACSL4 activates polyunsaturated fatty acids and sensitizes cancer cells to ferroptosis in immunotherapy-relevant settings.

FSP1 is a glutathione-independent ferroptosis suppressor.

Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids. To date, ferroptosis has been thought to be controlled only by the phospholipid hydroperoxide-reducing enzyme glutathione peroxidase 4 (GPX4) and radical-trapping antioxidants. However, elucidation of the factors that underlie the sensitivity of a given cell type to ferroptosis is crucial to understand the pathophysiological role of ferroptosis and how it may be exploited for the treatment of cancer.

Mechanism of metformin action in MCF-7 and MDA-MB-231 human breast cancer cells involves oxidative stress generation, DNA damage, and transforming growth factor β1 induction.

The participation of oxidative stress in the mechanism of metformin action in breast cancer remains unclear. We investigated the effects of clinical (6 and 30 μM) and experimental concentrations of metformin (1000 and 5000 μM) in MCF-7 and in MDA-MB-231 cells, verifying cytotoxicity, oxidative stress, DNA damage, and intracellular pathways related to cell growth and survival after 24 h of drug exposure. Clinical concentrations of metformin decreased metabolic activity of MCF-7 cells in the MTT assay, which showed increased oxidative stress and DNA damage, although cell death and impairment in the proliferative capacity were observed only at higher concentrations.

Nitric oxide is responsible for oxidative skin injury and modulation of cell proliferation after 24 hours of UVB exposures.

Nitric oxide (NO) is produced by various mammalian cells and plays a variety of regulatory roles in normal physiology and in pathological processes. This article provides evidence regarding the participation of NO in UVB-induced skin lesions and in the modulation of skin cell proliferation following UVB skin irradiation. Hairless mice were subjected to UVB irradiation for 3 hours and the skin evaluated immediately, 6 and 24 hours postirradiation.