Iron induces cell death and strengthens the efficacy of anti-androgen therapy in prostate cancer models

Iron induces cell death and strengthens the efficacy of anti-androgen therapy in prostate cancer models:

Purpose: In search of novel strategies to improve the outcome of advanced prostate cancer (PCa), we considered that PCa cells rearrange iron homeostasis, favoring iron uptake and proliferation. We exploited this adaptation by exposing PCa preclinical models to high-dose iron to induce toxicity and disrupt adaptation to androgen starvation. Experimental Design: We analyzed markers of cell viability and mechanisms underlying iron toxicity in androgen receptor-positive VCaP and LNCaP, castration-resistant DU-145 and PC-3, and murine TRAMP-C2 cells treated with iron and/or the anti-androgen bicalutamide. We validated the results in vivo in VCaP and PC-3 xenografts and in TRAMP-C2 injected mice treated with iron and/or bicalutamide. Results: Iron was toxic for all PCa cells. In particular, VCaP, LNCaP and TRAMP-C2 were highly iron-sensitive. Toxicity was mediated by oxidative stress, which primarily affected lipids, promoting ferroptosis. In highly sensitive cells, iron additionally caused protein damage. High-basal iron content and oxidative status defined high iron-sensitivity. Bicalutamide-iron combination exacerbated oxidative damage and cell death, triggering protein oxidation also in poorly iron-sensitive DU-145 and PC-3 cells. In vivo, iron reduced tumor growth in TRAMP-C2 and VCaP mice. In PC-3 xenografts, bicalutamide-iron combination caused protein oxidation and successfully impaired tumor expansion while single compounds were ineffective. Macrophages influenced body iron distribution but did not limit the iron effect on tumor expansion. Conclusions: Our models allow us to dissect the direct iron effect on cancer cells. We demonstrate the proof of principle that iron toxicity inhibits PCa cell proliferation, proposing a novel tool to strengthen anti-androgen treatment efficacy.