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  • br Introduction The nature of chemotherapies is to

    2022-01-14


    Introduction The nature of chemotherapies is to relieve the tumor burden of the patients by eliminating cancer Clindamycin HCl via inducing cell death, mostly regulated cell death represented by apoptosis [1,2]. Dozens of anticancer agents including clinically used ones kill cancer cells by promoting apoptosis directly or indirectly. However, as an endogenous barrier that must be subdued or bypassed before cellular transformation, apoptosis, in many cases, is compromised due to augmented antiapoptotic signaling or loss of proapoptotic mechanisms, rendering cancer cells resistant to many apoptosis-inducing chemotherapies [3,4]. Therefore, it is plausible to target an alternative cell death pathway that obviates the need for an intact apoptosis signaling cascade. In recent years, a noncanonical form of regulated cell death, namely ferroptosis, has shown great promise to extend current apoptosis-based chemotherapies. Ferroptosis was first defined by Stockwell’s group in 2012 as a cell death subroutine caused by an iron-dependent irreversible accumulation of lipid peroxides [5,6]. Under normal conditions, the oxidized lipid arising from interactions with reactive oxygen species (ROS) generated by iron-dependent Fenton reaction can be converted to non-toxic lipid alcohols by glutathione peroxidase 4 (GPX4) (Fig. 1), whereas in the context of excess iron ions or dysfunctional GPX4, lipid peroxides can reach to a cytotoxic level that eventually initiates ferroptosis [7]. Since cancer cells are already heavily burdened with oxidative stress due to their highly active metabolic processes, which manifests as elevated hydrogen peroxide (H2O2) in the tumor microenvironment [8], it is anticipated that they will be hypersensitive to dysregulated uptake of iron ions causing ROS overproduction, and to GPX4 inactivation impairing cellular tolerance to oxidative damage [9,10]. Hence, as a cell death pathway intimately involving oxidative Clindamycin HCl stress, ferroptosis appears to be an attractive rationale for developing anticancer drugs [11]. Indeed, numerous studies have demonstrated the effectiveness of cancer-killing by inducing ferroptosis, which is mainly accomplished by elevating the intracellular ROS levels and inactivating the activity of GPX4 [[12], [13], [14]]. Interestingly, elevated intracellular ROS level is often observed as an attendant effect of some chemotherapeutic drugs such as doxorubicin and hydroxyurea [15,16]. However, anticancer agents that act primarily by increasing ROS production are rarely seen, largely because of the lack of a tumor-specific target that can minimize damage to normal tissues [17]. With our increasing understanding of ferroptosis, a number of ROS-producing agents have now been tested for their ability to trigger cell death by ferroptosis, most of which are based on intracellular Fenton reaction that involves ferrous ion (Fe2+) or ferric iron (Fe3+)-mediated catalytic degradation of H2O2 into strong oxidative hydroxyl radical (HO•) [[18], [19], [20]]. Of note, to improve the tumor specificity of ferroptosis-inducing agents, tumor-responsive nanomaterials are frequently employed [21]. Given the central role of iron in ferroptosis, much effort has been put into iron-based nanomaterials such as ferumoxytol [22], amorphous iron nanoparticles [23] and iron-organic frameworks [24], which effectively induce ferroptosis under experimental conditions. However, extremely low pH (2–4) and high Fe dose (75 mg Fe/kg) are required for optimal Fenton reaction to elicit ferroptosis, rendering it very difficult for these agents to be used clinically as a standalone drug [18,19,23]. In addition, non-ferrous metals with multiple oxidation states, such as manganese [25] and copper [26], have also been used to design ferroptosis-inducing agents, demonstrating the flexibility of ferroptosis-based therapeutics. While the main strategy to exacerbate ROS burden is to apply iron-based nanomaterials, inactivation of GPX4 heavily relies on small molecules such as the erastin, sorafenib, and sulfasalazine. These agents can inhibit the cysteine/glutamate transporter system xc-, leading to depletion of the GPX4 substrate glutathione (GSH) and thus GPX4 inhibition [[27], [28], [29]]. Besides, genetic manipulation of GPX4, ACSL4, p53, and SLC7A11 have also shown effective in mounting ferroptosis, though limited by a lack of delivery system that is both efficient and safe enough [[30], [31], [32], [33]].