Erastin, a ferroptosis-inducing agent, sensitized cancer cells to X-ray irradiation via glutathione starvation in vitro and in vivo

Abstract

High concentrations of antioxidants in cancer cells are huge obstacle in cancer radiotherapy. Erastin was first discovered as an inducer of iron-dependent cell death called ferroptosis accompanied by antioxidant depletion caused by cystine glutamate antiporter inhibition. Therefore, treatment with erastin is expected to potentially enhance cellular radiosensitivity. In this study, we investigated the influence of treatment with erastin on the radiation efficiency against cancers. The clonogenic ability, glutathione peroxidase 4 (GPX4) expression, and glutathione concentration were evaluated using HeLa and NCI-H1975 adenocarcinoma cell lines treated with erastin and/or X-ray irradiation. For in vivo studies, NCI-H1975 cells were transplanted in the left shoulder of nude mice, and then radiosensitizing effect of erastin and glutathione concentration in the cancer were evaluated. Treatment with erastin induced ferroptosis and decreased the concentration of glutathione and GPX4 protein expression levels in the two tumor cell lines. Moreover, erastin enhanced X-ray irradiation-induced cell death in both human tumor cell lines. Furthermore, erastin treatment of a tumor-transplanted mouse model similarly demonstrated the radiosensitizing effect and decrease in intratumoral glutathione concentration in the in vitro study. In conclusion, our study demonstrated the radiosensitizing effect of erastin on two adenocarcinoma cell lines and the tumor xenograft model accompanied by glutathione depletion, indicating that ferroptosis inducers that reduce glutathione concentration could be applied as a novel cancer therapy in combination with radiotherapy.

The ferroptosis and iron-metabolism signature robustly predicts clinical diagnosis, prognosis and immune microenvironment for hepatocellular carcinoma

“…As an inducer of ferroptosis, erastin was used to evaluate its influence on the development and progression of HCC [ 37 ]. The chemical formula of erastin was showed in Fig.…”

Ferroptosis and Cancer: Mitochondria Meet the “Iron Maiden” Cell Death

“…Among the abovementioned drugs RSL3 and erastin, the two main ferroptosis inducers have been used in a variety of tumor models in vitro [114,115]. Both drugs, however, do not meet the pharmacokinetic standards for in vivo application and need to be further optimized for clinical application [116].…”

The ferroptosis and iron-metabolism signature robustly predicts clinical diagnosis, prognosis and immune microenvironment for hepatocellular carcinoma

“…Inhibition of erastin on the proliferation and tumorigenesis of HCC and its possible molecular mechanism As an inducer of ferroptosis, erastin was used to evaluate its in uence on the development and progression of HCC [37].The chemical formula of erastin was showed in Figure 10A. Performing the CCK-8 assay, we found that erastin treatment inhibited cell proliferation in a dose-dependent manner ( Figure 10B-C).…”