erastin and Prostatic-Neoplasms--Castration-Resistant

Ferroptosis is a type of programmed cell death induced by the accumulation of lipid peroxidation and lipid reactive oxygen species in cells. It has been recently demonstrated that cancer cells are vulnerable to ferroptosis inducers (FIN). However, the therapeutic potential of FINs in prostate cancer in preclinical settings has not been explored. In this study, we demonstrate that mediators of ferroptosis, solute carrier family 7 member 11, SLC3A2, and glutathione peroxidase, are expressed in treatment-resistant prostate cancer. We further demonstrate that treatment-resistant prostate cancer cells are sensitive to two FINs, erastin and RSL3. Treatment with erastin and RSL3 led to a significant decrease in prostate cancer cell growth and migration

Topics: Amino Acid Transport System y+; Androgen Antagonists; Androstenes; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Carbolines; Cell Line, Tumor; Drug Resistance, Neoplasm; Ferroptosis; Fusion Regulatory Protein 1, Heavy Chain; Humans; Male; Mice; Neoplasm Staging; Nitriles; Phenylthiohydantoin; Phospholipid Hydroperoxide Glutathione Peroxidase; Piperazines; Prostate; Prostatic Neoplasms, Castration-Resistant; Xenograft Model Antitumor Assays

To date, there is no effective therapy available for the treatment of castration‑resistant prostate cancer (CRPC), and patients generally succumb to the disease within 2 to 4 years. In the progression of CRPC, androgen receptor (AR) and its splice variants play critical roles. Hence, it is necessary to develop a drug to inhibit the expression and activity of the full‑length and splice variants of AR for the treatment of CRPC. Erastin, as the first discovered drug to induce ferroptosis, has been studied in various types of cancer. However, there are few studies focusing on the relationship between erastin and AR. In the present study, western blotting, and sulforhodamine B cell viability, glutathione, lipid peroxidation and reactive oxygen species assays were performed to verify the ferroptosis of CRPC cells; reverse transcription‑quantitative polymerase chain reaction, dual‑luciferase reporter, and lentiviral packaging and lentivirus‑infected cell assays were employed to evaluate how erastin affects AR. A mouse xenograft assay was used to determine the underlying mechanism in vivo. Erastin, as a classical inducer of ferroptosis, can suppress the transcriptional activities of both the full‑length and splice variants in AR models in vitro and in vivo. In addition, when erastin was used for CRPC treatment combined with docetaxel, the growth inhibitory efficacy of docetaxel was found to be enhanced. Thus, these findings indicated that ferroptosis inducer erastin has potential in the treatment of CRPC via targeting AR.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Survival; Docetaxel; Down-Regulation; Drug Synergism; Ferroptosis; Gene Expression Regulation, Neoplastic; Humans; Lipid Peroxidation; Male; Mice; Piperazines; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Reactive Oxygen Species; Receptors, Androgen; Xenograft Model Antitumor Assays