Ferroptosis is a newly discovered type of cell death that differs from traditional apoptosis and necrosis and results from iron‐dependent lipid peroxide accumulation. Ferroptotic cell death is characterized by cytological changes, including cell volume shrinkage and increased mitochondrial membrane density. Ferroptosis can be induced by two classes of small‐molecule substances known as class 1 (system X c − inhibitors) and class 2 ferroptosis inducers [glutathione peroxidase 4 (GPx4) inhibitors]. In addition to these small‐molecule substances, a number of drugs (e.g. sorafenib, artemisinin and its derivatives) can induce ferroptosis. Various factors, such as the mevalonate (MVA) and sulphur‐transfer pathways, play pivotal roles in the regulation of ferroptosis. Ferroptosis plays an unneglectable role in regulating the growth and proliferation of some types of tumour cells, such as lymphocytoma, ductal cell cancer of the pancreas, renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Here, we will first introduce the discovery of and research pertaining to ferroptosis; then summarize the induction mechanisms and regulatory pathways of ferroptosis; and finally, further elucidate the roles of ferroptosis in human tumourous diseases.

Cadmium is one of the most toxic metal compounds found in the environment. It is well established that Cd induces hepatotoxicity in humans and multiple animal models. Melatonin, a major secretory product of the pineal gland, has been reported to protect against Cd-induced hepatotoxicity. However, the mechanism behind this protection remains to be elucidated. We exposed HepG2 cells to different concentrations of cadmium chloride (2.5, 5, and 10 μM) for 12 h. We found that Cd induced mitochondrial-derived superoxide anion-dependent autophagic cell death. Specifically, Cd decreased SIRT3 protein expression and activity and promoted the acetylation of SOD2, superoxide dismutase 2, mitochondrial, thus decreasing its activity, a key enzyme involved in mitochondrial ROS production, although Cd did not disrupt the interaction between SIRT3 and SOD2. These effects were ameliorated by overexpression of SIRT3. However, a catalytic mutant of SIRT3 (SIRT3H248Y) lacking deacetylase activity lost the capacity to suppress Cd-induced autophagy. Notably, melatonin treatment enhanced the activity but not the expression of SIRT3, decreased the acetylation of SOD2, inhibited mitochondrial-derived O2•− production and suppressed the autophagy induced by 10 μM Cd. Moreover, 3-(1H-1,2,3-triazol-4-yl)pyridine, a confirmed selective SIRT3 inhibitor, blocked the melatonin-mediated suppression of autophagy by inhibiting SIRT3-SOD2 signaling. Importantly, melatonin suppressed Cd-induced autophagic cell death by enhancing SIRT3 activity in vivo. These results suggest that melatonin exerts a hepatoprotective effect on mitochondrial-derived O2•−-stimulated autophagic cell death that is dependent on the SIRT3/SOD2 pathway.

The development of intensity-modulated radiotherapy (IMRT) has created a clear need for a dosimeter that can accurately and conveniently measure dose distributions in three dimensions to assure treatment quality. PRESAGE™ is a new three dimensional (3D) dosimetry material consisting of an optically clear polyurethane matrix, containing a leuco dye that exhibits a radiochromic response when exposed to ionizing radiation. A number of potential advantages accrue over other gel dosimeters, including insensitivity to oxygen, radiation induced light absorption contrast rather than scattering contrast, and a solid texture amenable to machining to a variety of shapes and sizes without the requirement of an external container. In this paper, we introduce an efficient method to investigate the basic properties of a 3D dosimetry material that exhibits an optical dose response. The method is applied here to study the key aspects of the optical dose response of PRESAGE™: linearity, dose rate dependency, reproducibility, stability, spectral changes in absorption, and temperature effects. PRESAGE™ was prepared in 1×1×4.5 cm 3 optical cuvettes for convenience and was irradiated by both photon and electron beams to different doses, dose rates, and energies. Longer PRESAGE™ columns (2 ×2×13 cm 3 ) were formed without an external container, for measurements of photon and high energy electron depth-dose curves. A linear optical scanning technique was used to detect the depth distribution of radiation induced optical density (OD) change along the PRESAGE™ columns and cuvettes. Measured depth-OD curves were compared with percent depth dose (PDD). Results indicate that PRESAGE™ has a linear optical response to radiation dose (with a root mean square error of ∼1%), little dependency on dose rate (∼2%), high intrabatch reproducibility (<2%), and can be stable (∼2%) during 2 hours to 2 days post irradiation. Accurate PRESAGE™ dosimetry requires temperature control within 1 °C. Variations in the PRESAGE™ formulation yield corresponding variations in sensitivity, stability, and density. CT numbers in the range 100-470 were observed. In conclusion, the small volume studies presented here indicate PRESAGE™ to be a promising, versatile, and practical new dosimetry material with applicability for radiation therapy.

There is a pressing need for a practical three-dimensional (3D) dosimetry system, convenient for clinical use, and with the accuracy and resolution to enable comprehensive verification of the complex dose distributions typical of modern radiation therapy. Here we introduce a dosimetry system that can achieve this challenge, consisting of a radiochromic dosimeter (PRESAGE™) and a commercial optical computed tomography (CT) scanning system (OCTOPUS™). PRESAGE™ is a transparent material with compelling properties for dosimetry, including insensitivity of the dose response to atmospheric exposure, a solid texture negating the need for an external container (reducing edge effects), and amenability to accurate optical CT scanning due to radiochromic optical contrast as opposed to light-scattering contrast. An evaluation of the performance and viability of the PRESAGE™/OCTOPUS, combination for routine clinical 3D dosimetry is presented. The performance of the two components (scanner and dosimeter) was investigated separately prior to full system test. The optical CT scanner has a spatial resolution of ≤1 mm, geometric accuracy within 1 mm, and high reconstruction linearity (with a R 2 value of 0.9979 and a standard error of estimation of ~1%) relative to independent measurement. The overall performance of the PRESAGE™/ OCTOPUS system was evaluated with respect to a simple known 3D dose distribution, by comparison with GAFCHROMIC ® EBT film and the calculated dose from a commissioned planning system. The "measured" dose distribution in a cylindrical PRESAGE™ dosimeter (16 cm diameter and 11 cm height) was determined by optical-CT, using a filtered backprojection reconstruction algorithm. A three-way Gamma map comparison (4% dose difference and 4 mm distance to agreement), between the PRESAGE™, EBT and calculated dose distributions, showed full agreement in measurable region of PRESAGE™ dosimeter (~90% of radius). The EBT and PRESAGE™ distributions agreed more closely with each other than with the calculated plan, consistent with penumbral blurring in the planning data which was acquired with an ion chamber. In summary, our results support the conclusion that the PRESAGE™ optical-CT combination represents a significant step forward in 3D dosimetry, and provides a robust, clinically effective and viable high-resolution relative 3D dosimetry system for radiation therapy.

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