Iron supplementation enhances RSL3-induced ferroptosis to treat naïve and prevent castration-resistant prostate cancer

Abstract

Prostate cancer (PCa) is a leading cause of death in the male population commonly treated with androgen deprivation therapy that often relapses as androgen-independent and aggressive castration-resistant prostate cancer (CRPC). Ferroptosis is a recently described form of cell death that requires abundant cytosolic labile iron to promote membrane lipid peroxidation and which can be induced by agents that inhibit the glutathione peroxidase-4 activity such as RSL3. Exploiting in vitro and in vivo human and murine PCa models and the multistage transgenic TRAMP model of PCa we show that RSL3 induces ferroptosis in PCa cells and demonstrate for the first time that iron supplementation significantly increases the effect of RSL3 triggering lipid peroxidation, enhanced intracellular stress and leading to cancer cell death. Moreover, the combination with the second generation anti-androgen drug enzalutamide potentiates the effect of the RSL3 + iron combination leading to superior inhibition of PCa and preventing the onset of CRPC in the TRAMP mouse model. These data open new perspectives in the use of pro-ferroptotic approaches alone or in combination with enzalutamide for the treatment of PCa.

RSL3 enhances ROS-mediated cell apoptosis of myelodysplastic syndrome cells through MYB/Bcl-2 signaling pathway

“…After the tumor volume increased to 50–100 mm 3 , the mice were divided into the RSL3-treated group and the control group. RSL3 (20 mg/kg) or vehicle was administered intraperitoneally into mice once every two days [ 35 , 36 ]. It was shown that tumor volume and weight were markedly smaller in RSL3-treated mice than control mice, while the body weight did not differ significantly between the RSL3-treated group and control group, indicating the safety of RSL3 administration (Fig.…”

Increased ferroptosis in leukocytes from preeclamptic women involving the long non‐coding taurine upregulated gene 1 (TUG1)

“…However, local iron overload caused ferroptosis in the decidual stromal cells by downregulating GSH and GPX4 levels [40]. An exogenous supplement of iron increased the sensitivity of cells to ferroptosis inducers [41] and enhanced RSL3-induced ferroptosis [42] in vitro. Future studies should evaluate if iron-supplementation in pregnancy may impact ferroptosis in vivo.…”

Icariin‑curcumol promotes ferroptosis in prostate cancer cells through Nrf2/HO‑1 signaling

“…Ferroptosis has been implicated in several human diseases, including PCa ( 4 ). Increasing evidence indicates that ferroptosis inhibits tumor growth ( 5 ) and the employment of ferroptosis inducers or targeting ferroptosis-related genes may represent promising strategies for treating castration-resistant PCa (CRPC) ( 6 ). Traditional Chinese medicine has multiple targets and can regulate various signaling pathways, including ADAMTS18( 7 ), reactive oxygen species (ROS) ( 8 ), nuclear factor erythroid 2-related factor 2 (Nrf2) ( 9 ) and glutathione peroxidase 4 (GPX4) ( 10 ), thereby modulating ferroptosis.…”