Ferroptosis Inducers Are a Novel Therapeutic Approach for Advanced Prostate Cancer

Abstract

Ferroptosis is a type of programmed cell death induced by the accumulation of lipid peroxidation and lipid reactive oxygen species (ROS) in cells. It has been recently demonstrated that cancer cells are vulnerable to ferroptosis inducers (FIN). However, the therapeutic potential of ferroptosis inducers in prostate cancer in pre-clinical settings has not been explored. In this study, we demonstrate that mediators of ferroptosis SLC7A11, SLC3A2 and GPX4 are expressed in treatment-resistant prostate cancer. We further demonstrate that treatment-resistant prostate cancer cells are sensitive to two ferroptosis inducers, erastin and RSL3. Treatment with erastin and RSL3 led to a significant decrease in prostate cancer cell growth and migration in vitro and significantly delayed the tumor growth of treatment-resistant prostate cancer in vivo, with no measurable side effects. Combination of erastin or RSL3 with standard-of-care second-generation anti-androgens for advanced prostate cancer halted prostate cancer cell growth and migration in vitro and tumor growth in vivo. These results demonstrate the potential of erastin or RSL3 independently and in combination with standard-of-care second-generation anti-androgens as novel therapeutic strategies for advanced prostate cancer.

Identifying a Ferroptosis-Related Gene Signature for Predicting Biochemical Recurrence of Prostate Cancer

“…These observations suggest that PCa, as a lipid metabolic tumor, may be sensitive to ferroptosis. Ghoochani et al (2021) High-throughput gene sequencing technology for biological samples enables large-scale omics research. In this study, we tried to explore a genetic marker based on ferroptosis to predict the BCR of PCa.…”

“…Qin et al (2021) designed and synthesized an isothiocyanate-containing hybrid AR antagonist that can efficiently downregulate AR/AR splice variant and induce ferroptosis in CRPC cells combined with glutathione (GSH) synthesis inhibitor. There was a suggestion that the induction of ferroptosis is a new therapeutic strategy for advanced PCa, which can be used as a monotherapy or as a combination therapy with second-generation antiandrogens (Ghoochani et al, 2021). However, the effect of ferroptosis on the prognosis of PCa has rarely been reported.…”

Ferroptosis and Its Potential Role in Metabolic Diseases: A Curse or Revitalization?

“…Adrenocortical carcinomas (ACCs) are also sensitive to the induction of ferroptosis, and based on this result, a new therapeutic target to ACCs may present beyond the mitotane who cannot energize the ferroptosis pathway (Belavgeni et al, 2019). Additionally, due to prostate cancer cells' high sensitivity to iron toxicity, activating ferroptosis appears to be a new strategy for treating advanced prostate cancer, with an option to include second-generation anti-androgens (Bordini et al, 2020;Ghoochani et al, 2021). As an FDA-approved anthelmintic, flubendazole was found to target P53 to induce ferroptosis in an effort to delay the development of prostate cancer (Zhou et al, 2021).…”

Oncogene-mediated metabolic gene signature predicts breast cancer outcome

“…Totally, 5 × 10 4 cells were mixed with 10 μl Matrigel and plated in a 24-well plate as a single droplet in the middle of a well as it is described previously 34,[51][52][53] . After 20 min of incubation at 37 °C, the Matrigel was solidified, and the media was added.…”