Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Stanford, California.
Department of Urology, University of Washington, Seattle, Washington.
Cancer Res. 2021 Mar 15;81(6):1583-1594. doi: 10.1158/0008-5472.CAN-20-3477. Epub 2021 Jan 22.
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 and significantly delayed the tumor growth of treatment-resistant prostate cancer , with no measurable side effects. Combination of erastin or RSL3 with standard-of-care second-generation antiandrogens for advanced prostate cancer halted prostate cancer cell growth and migration and tumor growth . These results demonstrate the potential of erastin or RSL3 independently and in combination with standard-of-care second-generation antiandrogens as novel therapeutic strategies for advanced prostate cancer. SIGNIFICANCE: These findings reveal that induction of ferroptosis is a new therapeutic strategy for advanced prostate cancer as a monotherapy and in combination with second-generation antiandrogens.
铁死亡是一种由细胞内脂质过氧化和脂质活性氧积累引起的程序性细胞死亡。最近有研究表明，癌细胞对铁死亡诱导剂（FIN）敏感。然而，在临床前环境中，FIN 在前列腺癌中的治疗潜力尚未得到探索。在这项研究中，我们证明了铁死亡的介质，溶质载体家族 7 成员 11（SLC3A2）和谷胱甘肽过氧化物酶在耐药性前列腺癌中表达。我们进一步证明，耐药性前列腺癌细胞对两种 FIN，erastin 和 RSL3 敏感。用 erastin 和 RSL3 处理导致前列腺癌细胞生长和迁移显著减少，并显著延迟耐药性前列腺癌的肿瘤生长，没有可测量的副作用。将 erastin 或 RSL3 与标准治疗的第二代抗雄激素联合用于晚期前列腺癌，可阻止前列腺癌细胞生长和迁移，并抑制肿瘤生长。这些结果表明，erastin 或 RSL3 具有独立的潜力，并与标准治疗的第二代抗雄激素联合应用，为晚期前列腺癌提供了一种新的治疗策略。意义：这些发现表明，诱导铁死亡是一种新的治疗晚期前列腺癌的策略，可作为单一疗法和与第二代抗雄激素联合应用。
