Unlocking ferroptosis in prostate cancer - the road to novel therapies and imaging markers.

Ferroptosis is a distinct form of regulated cell death that is predominantly driven by the build-up of intracellular iron and lipid peroxides. Ferroptosis suppression is widely accepted to contribute to the pathogenesis of several tumours including prostate cancer. Results from some studies reported that prostate cancer cells can be highly susceptible to ferroptosis inducers, providing potential for an interesting new avenue of therapeutic intervention for advanced prostate cancer. In this Perspective, we describe novel molecular underpinnings and metabolic drivers of ferroptosis, analyse the functions and mechanisms of ferroptosis in tumours, and highlight prostate cancer-specific susceptibilities to ferroptosis by connecting ferroptosis pathways to the distinctive metabolic reprogramming of prostate cancer cells. Leveraging these novel mechanistic insights could provide innovative therapeutic opportunities in which ferroptosis induction augments the efficacy of currently available prostate cancer treatment regimens, pending the elimination of major bottlenecks for the clinical translation of these treatment combinations, such as the development of clinical-grade inhibitors of the anti-ferroptotic enzymes as well as non-invasive biomarkers of ferroptosis. These biomarkers could be exploited for diagnostic imaging and treatment decision-making.

Short-chain per- and polyfluoralkyl substances (PFAS) effects on oxidative stress biomarkers in human liver, kidney, muscle, and microglia cell lines.

Long-chain per- and polyfluoralkyl substances (PFAS) are ubiquitous contaminants implicated in the induction of intracellular reactive oxygen species (ROS), compromising antioxidant defense mechanisms in vitro and in vivo. While a handful of studies have assessed oxidative stress effects by PFAS, few specifically address short-chain PFAS. We conducted an evaluation of oxidative stress biomarkers in vitro following exposures to low (1 nM) and high (1 µM) concentrations of five short-chain PFAS compounds: perfluorobutanesulfonic acid (PFBS), perfluorohexanoic acid (PFHxA), [undecafluoro-2-methyl-3-oxahexanoic acid (HFPO-DA)], 6:2 fluorotelomer alcohol (6:2 FTOH) and perfluorohexanesulfonic acid (PFHxS). We conducted experiments in human kidney (HEK293-hTLR2), liver (HepaRG), microglia (HMC-3), and muscle (RMS-13) cell lines. Fluorescence microscopy measurements in HepaRG cells indicated ROS generation in cells exposed to PFBS and PFHxA for 24 h. Antioxidant enzyme activities were determined following 24 h short-chain PFAS exposures in HepaRG, HEK293-hTLR2, HMC-3, and RMS-13. Notably, exposure to PFBS for 24 h increased the activity of GPX in all four cell types at 1 µM and 1 nM in HepaRG and RMS-13 cells. Every short-chain PFAS evaluated, except for PFHxS, increased the activity of at least one antioxidant enzyme. To our knowledge, this is the first study of its kind to explore antioxidant defense alterations to microglia and muscle cell lines by PFAS. The findings of this study hold great potential to contribute to the limited understanding of short-chain PFAS mechanisms of toxicity and provide data necessary to inform the human health risk assessment process.

Comparative cytotoxicity of seven per- and polyfluoroalkyl substances (PFAS) in six human cell lines.

Human exposures to perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been linked to several diseases associated with adverse health outcomes. Animal studies have been conducted, though these may not be sufficient due to the inherent differences in metabolic processes between humans and rodents. Acquiring relevant data on the health effects of short-chain PFAS can be achieved through methods supported by in vitro human cell-based models. Specifically, cytotoxicity assays are the crucial first step to providing meaningful information used for determining safety and providing baseline information for further testing. To this end, we exposed human cell lines representative of six different tissue types, including colon (CaCo-2), liver (HepaRG), kidney (HEK293), brain (HMC-3), lung (MRC-5), and muscle (RMS-13) to five short-chain PFAS and two legacy PFAS. The exposure of the individual PFAS was assessed using a range of concentrations starting from a low concentration (10-11 M) to a high concentration of (10-4 M). Our results indicated that CaCo-2 and HEK293 cells were the least sensitive to PFAS exposure, while HMC-3, HepaRG, MRC-5, and RMS-13 demonstrated significant decreases in viability in a relatively narrow range (EC50 ranging from 1 to 70 µM). The most sensitive cell line was the neural HMC-3 for all short- and long-chain PFAS (with EC50 ranging from 1.34 to 2.73 µM). Our data suggest that PFAS do not exert toxicity on all cell types equally, and the cytotoxicity estimates we obtained varied from previously reported values. Overall, this study is novel because it uses human cell lines that have not been widely used to understand human health outcomes associated with PFAS exposure.