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  • br Other strategies for ferroptosis In addition to ROS gener

    2022-05-19


    Other strategies for ferroptosis In addition to ROS-generating and GPX4 inactivating nanomaterials, small molecules and genetic manipulation targeting key factors in the ferroptosis pathway have also been tested for their anticancer effects [39,47,48]. Among a myriad of proteins involved in ferroptosis, system xc- may be the most studied target for small molecule-based intervention. System xc- is a cystine/glutamate antiporter transporting cysteine into cells, which is a rate-limiting step in the biosynthesis of GSH [49]. Small molecules including erastin, sorafenib and sulfasalazine can inhibit the function of system xc- and therefore impair GSH synthesis, leading to GPX4 inactivation and eventually ferroptosis (Figs. 6a–c) [12,39,50]. CEP 1347 australia As to GPX4 itself, the small molecule (1S, 3R)-RSL3 can directly bind to it and inhibit its activity, which allows accumulation of lipid peroxides (Fig. 6d) [39,47]. The well-known tumor suppressor p53 also plays a central role in ferroptosis. Genetic manipulation of p53 shows that p53 knockdown renders cancer CEP 1347 australia resistant to oxidative stress, while its overexpression often synergizes with ferroptosis-inducing agents [51]. Jiang et al. observed that knockout of p53 protein could enhance the cell viability after the treatment of nutlin and ROS (Fig. 6e). SLC7A11 appears to be the downstream target of p53 to regulate ferroptosis, as shown that the p533KR-mediated tumor growth inhibition can be counteracted by the overexpression of SLC7A11 in a xenograft model (Fig. 6f) [30]. Recently, Doll et al. have identified ACSL4 as an integral component of the ferroptosis execution [52]. Notably, the expression of this protein is predictive of the sensitivity of basal-like breast cancer cells to ferroptosis. Since ACSL4 promotes ferroptosis in response to oxidative stress, overexpressing ACSL4 via plasmid DNA may confer a synergistic effect with other ferroptosis-inducing agents.
    Conclusions and perspectives Since ferroptosis was first identified in 2012, it has been intensively studied for its mechanisms. A number of distinct features of ferroptosis have distinguished it from other cell death pathways, including but not limited to lipid peroxides accumulation, elevated Ptgs2, overexpression of Acyl-CoA synthetase long-chain family member 4 (ACSL4), and upregulated cation transport regulator-like protein 1 (CHAC1), these features are also used as biomarkers to examine ferroptosis. The evolving knowledge of how this new form of regulated cell death is executed lays the foundation for various strategies for the ferroptosis-based tumor therapy [5,7,39,53,54]. This mini-review summarized the development and application of various ferroptosis-inducing agents for cancer therapy in recent years, including the Fenton reaction-based nanomaterials, GPX4-based nanomaterials, small molecules, and gene technologies. The small molecules and gene technologies mainly act by impairing the GPX4-centered antioxidation mechanism of cancer cells, which consequently causes a failure to convert toxic lipid peroxides to non-toxic lipid alcohols. Though displaying potent anticancer effects, the small molecules inevitably have adverse effects on normal tissues because of the lack of specificity. In addition, short blood half-lives of small molecules in vivo also limit their therapeutic performance in clinical settings. As for gene therapy, safety concerns about off-target effects and uncertain dose-effect relationship are still major obstacles to its further development [12]. Distinct from small molecules and gene technologies targeting the antioxidation mechanism, Fenton reaction-based nanomaterials exploit ferroptosis to kill cancer cells by generating excessive ROS. Up to now, iron-based nanomaterials are the most studied Fenton reaction-based ferroptosis-inducing agent, which can release iron ions to elevate the intracellular ROS burden. The plethora of intracellular ROS can overload the GPX4-mediated antioxidation activity, leading to irreversible accumulation of lipid peroxides and eventually cell death by ferroptosis. In order to improve their therapeutic efficiency, iron-based nanomaterials are usually used in combination with other ferroptosis-inducing agents, such as encapsulated H2O2 [55], lipid-hydroperoxide [56], and cisplatin [18].