Ferroptosis is a recently recognized form of cell death caused by accumulation of lipid peroxides. Studies have linked this form of cell death with a role in suppressing tumorigenesis within the human body.
Its role to prevent the formation of tumors can be exploited to treat human disease. Cancer therapy can utilize ferroptosis by identifying small molecules that activate ferroptosis or the inhibiting key molecules related to the process.
Recent studies have highlighted the ability of induced ferroptosis to enhance current chemotherapeutic treatments.
Ferroptosis and Cell Death
Ferroptosis is a mechanism of cell death that was discovered in 2012. It is caused by accumulation of iron-dependent lipid reactive oxygen species. The resulting oxidative degradation of lipids leads to cell membrane denaturation. Ferroptosis is induced when there is depletion of the antioxidant glutathione and a loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4). The process is dependent on intracellular iron acting as a catalyst to form free radicals from peroxides. The free radicals then degrade lipid molecules by the removing electrons.
Evidence for Ferroptosis as a Tumor Suppressor
The potential for a new cancer treatment began with the evidence that ferroptosis has a crucial role as a tumor suppressor.
Studies used GPX4 knockout mice to analyze cell death mechanisms after GPX4 inhibition. The knockout models displayed lipid peroxidation indicating that GPX4 protects cells from the damaging effects of lipid peroxides.
The cell death induced from GPX4 deletion indicates the presence of ferroptosis and that GPX4 is its central regulator.
Another study found that tumor suppressor p53 inhibits tumor growth by inducing ferroptosis along with cell cycle arrest and apoptosis. SLC7A11, the gene encoding cystine/glutamate antiporter system Xc−, can induce ferroptosis when inhibited. Ferroptosis can also be induced by p53 by the repression of SLC7A11.
Moreover, the acetylation-defective mutant, p533KR, retains the ability to induce ferroptosis when normal p53 functions fail to be induced.
The retained tumor suppression of p533KR is a further indication of the role ferroptosis to prevent tumorigenesis.
Small Molecule Induced Ferroptosis
The natural tumor suppressor function suggests that activation of ferroptosis can provide a new form of cancer treatment.
Studies have shown that small molecules can induce ferroptosis and enhance the sensitivity of chemotherapeutic drugs. The ferroptosis inducer erastin improved the effectiveness of chemotherapy drugs in certain cancer cells.
Erastin triggers ferroptosis by the inhibiting cystine/glutamate antiporter system Xc. Thus, erastin is most successful at inducing ferroptosis in cancers that are dependent on GPX4 and Xc−. This includes renal cell carcinoma, B cell derived lymphomas, and certain triple-negative breast cancer cells.
A 2015 study suggested that induced ferroptosis can overcome the problem of drug resistance in acute myeloid leukemia. The high recurrence rate of acute myeloid leukemia patients is related to drug resistance through mechanisms, such as impaired drug export transporters and altered drug target sites. Low dose erastin was found to enhance the cancer activity of two first-line chemotherapeutic drugs where it contributed to growth inhibition while overcoming drug resistance.
GPX4 Inhibitors as Potential Ferroptosis Treatments
Current studies are evaluating whether GPX4 inhibitors are potential candidates for cancer therapy. The small molecule RSL3 was found to inhibit GPX4 and induce ferroptosis, but the underlying structural basis for inhibition that could be replicated in engineered GPX4 inhibitors is currently unknown.
Recent developments in this area include identification of a ligand-binding site on GPX4 that covalently targets the active site selenocysteine and leads to the suppression of GPX4. Nonetheless, any potential treatments through GPX4 inhibitors will need to evaluate potential side effects and define any difference in sensitivity between normal and cancer cells.
- Lu, B. et al. 2018. The Role of Ferroptosis in Cancer Development and Treatment Response, Frontiers in Pharmacology, 8: 992. https://www.frontiersin.org/articles/10.3389/fphar.2017.00992/full
- Yu, H. et al. 2017. Ferroptosis, a new form of cell death, and its relationships with tumourous diseases, Journal of Cellular and Molecular Medicine, 21, pp. 648-657. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345622/
- Yu, Y. et al. 2015. The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents, Molecular and Cellular Oncology, 2, e1054549. https://www.ncbi.nlm.nih.gov/pubmed/27308510
- Yang, W.S. et al. 2016. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis, PNAS, 113, e4966-4975. https://www.ncbi.nlm.nih.gov/pubmed/27506793