Ferroptosis inducers for prostate cancer therapy

Lipid peroxidation-driven iron-dependent ferroptosis is a regulated cell death mechanism implicated in numerous disease, such as neurological diseases, kidney injury, ischemia, and tumors, including prostate cancer. The cellular mechanisms of ferrosptosis are strongly associated with iron, reactive oxygen species and aminoacid metabolic pathways. Several compounds, namely ferroptosis inducers, impact on these pathways and trigger ferroptosis by i) inhibiting Xc– transporter system, ii) impairing GPX4 functions and iii) oxidizing iron and polyunsaturated phospholipids. Preclinical studies showed that in combination with conventional anticancer drugs, ferroptosis inducers are effective in prostate cancer and in combating the progression towards the castration resistant disease. This review overviews the mechanisms implicated in ferroptosis and discusses the findings achieved in prostate cancer.

Glucocorticoid signaling delays castration-induced regression in murine models of prostate cancer

Androgen deprivation therapy (ADT) is the mainstay therapy for recurrent and advanced prostate cancer. While human prostate cancers initially regress following ADT, many tumors fail this therapy and recur. To understand the response of prostate cancers to ADT, we have employed high frequency ultrasound imaging to track the kinetics of tumor volume in murine models of prostate cancer. Previously, we showed that normal (non-tumor) prostate regression begins within two days of castration. Following castration, murine prostate cancers also regress but only after a delay of 3-14 days, dependent on initial tumor size. Delayed regression is observed in two distinct mouse models (MYC over-expression, PTEN-deficient) implying that the genetic lesion which initiates carcinogenesis does not play a role. Intra-tumoral androgen levels are undetectable 16 hours post-castration, arguing that residual androgen signaling is not the cause of delayed regression. Castration induces tumor cell proliferation during this period. There is an increase in the active glucocorticoids, as well as glucocorticoid receptor (GR) mRNA and protein and a set of GR-regulated genes. A selective GR inhibitor eliminates the delayed regression phenotype in both models. Thus, GR signaling is activated following castration and transiently enhances tumor proliferation. This response to ADT resembles the GR-dependent mechanism of escape for prostate cancers that are resistant to anti-androgen therapies and may provide mechanistic insight into the development of castration resistant prostate cancer. If ADT-induced GR signaling is similar in human prostate cancers, simultaneous blockade of GR and androgen receptor signaling could improve prostate cancer therapy.