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Nanotechnology-Mediated Radiation Therapy
Published in D. Sakthi Kumar, Aswathy Ravindran Girija, Bionanotechnology in Cancer, 2023
In the majority of the radiation-based cancer therapies, apoptosis takes the spotlight in causing cell death mechanisms; however, newer reports have started coming out to shift the focus toward whether cancer therapies can also induce other forms of cell death. In a study carried out by Lei G et al. demonstrated the link between ionizing radiation and a form of regulated cell death caused by lipid peroxidation called ferroptosis [58]. The authors analyzed that ionizing radiation in cancer cells led to the induction of reactive oxygen species (ROS) and upregulated expression of a lipid metabolizing enzyme ACSL4 to initiate ferroptosis. The study concluded that ferroptosis in cancer patients conferred better response and survival to radiotherapy.
Targeting stearoyl-coa desaturase enhances radiation induced ferroptosis and immunogenic cell death in esophageal squamous cell carcinoma
Published in OncoImmunology, 2022
Hui Luo, Xiaohui Wang, Shuai Song, Yunhan Wang, Qinfu Dan, Hong Ge
It was not until relatively recently that the role of RT in mediating cancer cell ferroptosis had started being investigated and analyzed.9,13 Lei et al. reported that RT was capable of inducing the production of reactive oxygen species and high expression of ACSL4, resulting in accumulation of lipid peroxidation and tumor cell ferroptosis.14 Similarly, RT-induced lipid peroxidation biosynthesis was detected in the present analysis. MF-438 was effective in inhibiting the production of POA and OA, resulted in impaired lipid metabolism; the combination of RT and MF-438 caused a great amount of intracellular lipid peroxidation accumulation. Immediately, cancer cell membrane structures were destroyed and it resulted in ferroptotic cell death. On the other hand, radiation-induced lipid peroxidation could be alleviated by treatment with exogenous monounsaturated fatty acids, resulting in protection from ferroptosis (Figure 7).
Hematopoietic protection and mechanisms of ferrostatin-1 on hematopoietic acute radiation syndrome of mice
Published in International Journal of Radiation Biology, 2021
Xiaohong Zhang, Mengxin Tian, Xin Li, Chunyan Zheng, Ailian Wang, Jundong Feng, Xiaodan Hu, Shuquan Chang, Haiqian Zhang
ACSL4 and lipoxygenase 15 are lipid metabolic enzymes. Ferroptosis has been previously associated with enzymatic lipid peroxidation. Changes in these two enzymes in total body radiation-induced ferroptosis and the effects of ferrostatin-1 on these two enzymes were evaluated. ACSL4 expression was found to be significantly decreased in irradiated BMMCs, and ferrostatin-1 mitigated the decrease in the level of ACSL4 (Figure 3(B)). This indicates that ACSL4 plays a role in total body radiation-induced ferroptosis, and ferrostatin-1 can target ACSL4. Although lipoxygenase 15 was also significantly decreased in irradiated BMMCs, its decrease was not attenuated by ferrostatin-1 (Figure 3(B)). This suggests that lipoxygenase 15 also participated in the lipid peroxidation of total body irradiation-induced ferroptosis, but ferrostatin-1 is unable to target lipoxygenase 15. Together, these indicate that ACSL4 and lipoxygenase 15 participated in the lipid peroxidation during total body radiation-induced ferroptosis, and ferrostatin-1 targets ACSL4 to mitigate lipid peroxidation.
Ferroptosis inhibition shields house ear institute-organ of corti 1 cells from free fatty acids-induced inflammatory injuries
Published in Acta Oto-Laryngologica, 2023
Xuemin Chen, Yiding Yu, Ning Yu, Weiwei Guo, Qingqing Jiang, Shiming Yang
Ferroptosis is mainly caused by the imbalance between the production and degradation of lipid ROS in the cell. Critical to the homeostasis of lipid oxidation-reduction reaction are system Xc- and GPX4 pathway. System Xc- is a heterodimer comprising of a light chain subunit SLC7A11 and a heavy chain subunit SLC3A2 [16]. SLC7A11 functions as a cystine/glutamate antiporter to transport extracellular cystine into the cytosol for GSH biosynthesis and antioxidant defense, which serves as a promising therapeutic target in multiple cancer therapy [17]. GPX4 belongs to the family of GPxs. It can utilize GSH as the reductant to directly eliminate toxic lipid hydroperoxides into lipid alcohols. The inhibition of GPX4 have been proposed to trigger ferroptosis in multiple diseases, including acute renal failure, osteoarthritis, gastric cancer and stroke. In this study, PA treatment decreased GPX4 and SLC7A11 expression at both mRNA and protein level, while ferroptosis inhibitors Fer-1 restored PA-blocked GPX4 and SLC7A11 expression, suggesting that loss of GPX4/SLC7A11-mediated antioxidant defense is implicated in PA-induced ferroptosis in HEI-OC1 cells. Besides, ACSL4 is a central enzyme ligating coenzyme A to polyunsaturated fatty acids (PUFA) to trigger phospholipids synthesis [18]. PTGS2 encodes COX-2, which is the rate-limiting enzyme for the conversion of arachidonic acid (AA) to prostaglandins (PGs), and responsible for amplifying inflammation through recruitment of macrophages [2]. Immune cell-mediated inflammation induced by NOX1 elicited the release of ROS, which is also regarded as ferroptosis-related molecules. Our results showed that these ferroptosis-related factors also participate in PA-induced ferroptosis, and upregulation of ACSL4 and PTGS2 mRNA were markedly prevented by Fer-1 treatment.