Citation: . A mini-review and perspective on ferroptosis-inducing strategies in cancer therapy[J]. Chinese Chemical Letters, ;2019, 30(4): 847-852. doi: 10.1016/j.cclet.2019.03.025 shu

A mini-review and perspective on ferroptosis-inducing strategies in cancer therapy

Received Date: 20 January 2019
Revised Date: 13 March 2019
Accepted Date: 16 March 2019
Available Online: 18 April 2019

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Ferroptosis, as a new type of cell death caused by lipid peroxidation, has attracted much attention since it was first identified in 2012. A lot of progress has been made in unraveling its mechanisms and therapeutic potential as a target for cancer therapy. Hitherto, there are mainly two strategies widely adopted for designing ferroptosis-inducing agents, which include increasing the intracellular reactive oxygen species (ROS) level by Fenton reaction, and inactivating the glutathione peroxidase 4 (GPX4). In this mini-review, we summarize the recent advances in ferroptosis-based anticancer treatments with a highlight on nanomaterials, and discuss the current challenges faced by those agents from the perspective of in vivo applications. Moreover, by generalizing ferroptosis induced by excess iron ions to cell death caused by the polyvalent metal-mediated oxidative burden, we introduce a new paradigm of cancer treatment by exploiting various polyvalent metals to disrupt the vulnerable redox balance in cancer cells, which may greatly diversify our arsenal to combat cancer.
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Figure 1. Pathways controlling ferroptosis. The ferroptosis intimately involves multiple pathways, including iron transportation, the amino acid metabolism, polyunsaturated fatty acid (PUFA) metabolism and the biosynthesis of glutathione. Free iron ions catalyze ROS production through Fenton reaction, leading to oxidation of phospholipid polyunsaturated fatty acids (PL-PUFA(PE)) into PL-PUFA (PE)-OOH. The PL-PUFA(PE)-OOH can be reduced to nontoxic alcohols by GPX4 under the normal circumstances. When there is excessive iron or GPX4 is inhibited, lipid peroxides will accumulate and eventually trigger ferroptosis. Copied with permission [7]. Copyright 2017, Elsevier.

Figure 2. (a) Preparation of AFeNPs. (b, c) Low- and high-resolution TEM images of AFeNPs. (d) Growth inhibitory effects of the AFeNPs on MCF-7 cells under indicated pH and H₂O₂ concentration (n = 6, mean ± s.d., ^**P < 0.01, and ^***P < 0.001). (e) Change of the H₂O₂ concentration in the tumor after different treatments (n = 3, mean ± s.d., ^*P < 0.05, and ^***P < 0.001). (f) Tumor volume curve after different treatments (n = 5, mean ± s.d., ^*P < 0.05, ^**P < 0.01 and ^***P < 0.001). (g) H&E staining images, LDI-MS ⁵⁶Fe mapping, and merged images of tumor tissues after i.v. AFeNP injection with or without magnetic targeting. The circles highlight the isolated pockets. Copied with permission [23]. Copyright 2016, John Wiley & Sons.

Figure 3. (a) The mechanism of MS@MnO₂ NPs as a smart chemodynamic agent for MRI-monitored chemo-chemodynamic combination therapy. (b) UV/vis absorption spectra and photo (inset) of MB after degradation by the Mn²⁺-mediated Fentonlike reaction in different solutions. (c) MB degradation in the presence of H₂O₂ plus GSH-treated MS@MnO₂ NPs. (d) Viability of U87MG cells after 24 h of incubation with MnCl₂ (Mn²⁺), MS@MnO₂ NPs, or MS@MnO₂-CPT. (e) Tumor growth curves of mice after intravenous injection with different formulations. Each dose of Mn: 4.0 mg/kg for 2 × MS@MnO₂ NPs group and 2.0 mg/kg for other groups. (f) TUNEL staining of tumor tissues from PBS and 2 × MS@MnO₂ NPs groups. Scale bar: 200 mm. Copied with permission [25]. Copyright 2018, John Wiley & Sons.

Figure 4. (a) Schematic illustration for MON-p53 mediated anticancer therapy. (b) Schematic illustration for the preparation of MON-p53. TEM images of PEI/p53 plasmid complex (c) and (d) MON-p53. (e) Deduced the mechanism of MON-p53 induced ferroptosis. (f) Viability of HT1080 cells treated as indicated, the concentrations are as following: MON-p53 ± ferrostatin-1 (Fer, 100 nmol/L), Ac-DEVD-CHO (Apo, 50 μmol/L), Necrostatin-1 (Nec, 490 nmol/L), 3-methyladenine (Aut, 60 μmol/L), deferoxamine (DFO, 100 μmol/L), glutamic (Glu, 1 μmol/L), cystine (Cys, 1 μmol/L), glutathione (GSH, 1 μmol/L), sodium ascorbate (VC, 20μmol/L), vitamin E (VE, 20 μmol/L); and treated with PEI/p53 ± Fer (100 nmol/L), Apo (50 μmol/L). (g) LPO, ROS, and NADP+/NADPH content of HT1080 cells treated with ferric chloride (Fe(Ⅲ), 10μmol/L; Fe(Ⅱ), 25 μmol/L), PEI/p53, Fe(Ⅱ)-MON-p53, and Fe(Ⅲ)-MON-p53. (h) Survival curves of mice receiving injections of Era at a dose of 5 mg/kg, MONP at 5 mg/kg, and DNA at 0.375 mg/kg (n = 7) in HT1080 tumorbearing mice. (ⅰ) HT1080 tumor volume curves of mice during in the first 25 days. Copied with permission [24]. Copyright 2017, American Chemical Society.

Figure 5. (a) Schematic illustration of the designed synthesis of the arginine-rich manganese silicate nanobubbles (AMSNs) and the in vivo tumor homing after blood circulation. Viability of Huh7 cells treated with AMSNs plus Fer-1 (b) or DFOM (c). (d) GSH/GSSG level in Huh7 cells treated with AMSNs for different durations. (e) GPX4 activity measured at different times after treatment with AMSNs. (f) Tumorgrowth inhibitory effects of the different treatments. (g) H&E and TUNEL staining of tumor slices obtained from BALB/C mice after various treatments. (Scale bar: 100 μm). Copied with permission [46]. Copyright 2018, American Chemical Society.

Figure 6. (a-d) Structures of the small-molecules used as ferroptosis-inducing agents in cancer therapy. (e) Bright field images of p53-proficient or -deficient U2OS cells treated with nutlin and ROS for 24 h. (f) SLC7A11 overexpression counteracts tumor growth suppression induced by p53^3KR in xenograft models. Copied with permission [30]. Copyright 2015, Springer Nature.

Figure 7. Schematic illustration for various metal ions with multiple oxidation states catalyzing the Fenton/Fenton-like reaction, in which H₂O₂ decomposes to highly oxidative reactive oxygen species.