Inaugurating a novel adjuvant therapy in urological cancers: Ferroptosis

Abstract

Ferroptosis, a distinctive form of programmed cell death, is involved in numerous diseases with specific characteristics, including certain cell morphology, functions, biochemistry, and genetics, that differ from other forms of programmed cell death, such as apoptosis. Many studies have explored ferroptosis and its associated mechanisms, drugs, and clinical applications in diseases such as kidney injury, stroke, ischemia-reperfusion injury, and prostate cancer. In this review, we summarize the regulatory mechanisms of some ferroptosis inducers, such as enzalutamide and erastin. These are current research focuses and have already been studied extensively. In summary, this review focuses on the use of ferroptosis induction as a therapeutic strategy for treating tumors of the urinary system.

Keywords: Ferroptosis; GPX4; Lipid; Prostatic cancer; ROS; Urinary system.

Graphical abstract

Figure 1

The history of ferroptosis research.

Figure 2

Mechanisms by which statins can induce ferroptosis and the synergy of BSO and ITC-ARi13.CoQ: Ubiquinone; GSH: Glutathione; PUFAs: Polyunsaturated fatty acids; PLOOH: Phospholipid hydroperoxide.

Figure 3

Ferroptosis induction-associated pathways of erastin and flubendazole. The three pathways by which erastin can induce ferroptosis are as follows: activating VDAC, inhibiting the cystine-glutamate transport of system Xc⁻, and activating p53. Flubendazole can activate p53 to trigger ferroptosis.GSH: Glutathione; ROS: Reactive oxygen species; PUFAs: Polyunsaturated fatty acids; VDACs: Voltage-dependent anion channels; PLOOH: Phospholipid hydroperoxide.

Figure 4

Signaling pathways by which sorafenib and ALZ003 can induce ferroptosis. Sorafenib induces ferroptotic cell death through two mechanisms: inhibiting system Xc⁻ and activating the p62-Keap1-Nrf2 pathway. In addition, trigonelline can enhance sorafenib-mediated ferroptosis by inhibiting Nrf2. ALZ003 leads to ferroptotic cell death through FBXL2-mediated AR ubiquitination. ICA II activates ferroptosis–regulatory pathways, including the PI3K-AKT-mTORC1 pathway, and the subsequent SREBP1/SCD1-mediated lipogenesis process.GSH: Glutathione; AR: Androgen receptor; AR: Androgen receptor; Keap1: Kelch-like ECH-associated protein 1; Keap1: Kelch-like ECH-associated protein 1; NQO1: Quinone oxidoreductase 1; FTH1: Ferritin heavy chain 1; PI3K: Phosphatidylinositol 3-kinase; PTEN: Phosphatase and tensin homolog deleted on chromosome 10; mTORC1: Mechanistic target of rapamycin C1; SCD1: Stearoyl-CoA desaturase-1; ICA II: Icariside II; AMPK: AMP-activated protein kinase, Nrf2: Nuclear factor erythroid-2 related factor 2.

Figure 5

Sulfasalazine can trigger ferroptosis through four mechanisms. Sulfasalazine can activate the TFR and inhibit system Xc⁻ simultaneously. Moreover, sulfasalazine can activate ferritinophagy and upregulate cellular labile iron levels to induce two pathways. ROS levels can be upregulated by Fe²⁺ to induce ferroptosis by facilitating lipid peroxidation and mediating AMPK phosphorylation, which consequently inhibits the nuclear translocation of SREBP1 and suppresses the transcription of BCAT2.GSH: Glutathione; AMPK: AMP-activated protein kinase; ROS: Reactive oxygen species; TFR: Transferrin receptor.