Another lever to efficiently eradicate tumors including

Another lever to efficiently eradicate tumors including ovarian cancer might rely on their high addiction to iron [34]. In fact, ultrasmall silica-based nanoparticles, functionalized with melanoma-targeting peptide, efficiently triggered ferroptosis not only in cell culture but also in tumor bearing mice, both of which could be fully inhibited by liproxstatin-1. The underlying molecular mechanisms were associated with cellular iron overload as these particles had a high propensity for adsorbing iron [31]. As described above, exploiting Fenton-based chemistry in killing tumor Bay 11-7085 by delivering engineered (and activatable) nanoparticles carrying toxic peroxide/iron cargos to tumors is indeed a highly active, upcoming field of research [96]. Another highly promising approach might be cystathionine-γ-lyase (CGL, cyst(e)inase)-mediated systemic deletion of cyst(e)ine, the building block of GSH biosynthesis [97]. In fact, administration of cyst(e)inase to cell, monkey and tumor bearing mice caused a robust deletion of L-cysteine and concomitant increases in cellular oxygen radical formation. This strategy proved highly efficient in suppressing the growth of prostate carcinoma allografts as well as tumor xenografts (breast and prostate) and robustly prolonged the survival of a leukemic B cell tumor model in vivo. In an era of personalized medicine and patient-centered cancer treatment, ferroptosis inducing strategies could also augment existing kinase inhibitor, antibody- and autoimmune-based therapies. Melanoma skin cancer originates from epidermal, pigment-producing melanocytes and advanced metastatic stages of the disease are currently associated with very poor prognosis. Highly plastic melanoma skin cancer cells potentially evade targeted immunotherapy by dedifferentiation, subsequently becoming more susceptible to ferroptosis-inducing agents, such as erastin, RSL3, ML162 and ML210 [98]. Along the same line, acquired drug resistance of therapy-resistant tumor cells of so-called “persister” cells was recently described to lead to a dependence on a functional GSH/GPX4 axis along a broad panel of cancer cells lines [99]. And in lung adenocarcinomas cysteine desulfurase (NFS1), an enzyme that removes sulfur from cysteine thereby providing inorganic sulfur, was found to be positively selected as this cancer entity is highly dependent on iron-sulfur cluster biosynthesis [100]. Consequently, shRNA-mediated suppression of NFS1 not only limits iron–sulfur cluster availability particularly under elevated oxygen tensions, but also predisposes MDA-MB-231 cells to ferroptosis.
Concluding remarks and future considerations During the last few years, substantial progress has been made in the understanding of the molecular and metabolic underpinnings of ferroptotic cell death. Studies performed in transgenic mice further allowed us to pinpoint which cells and tissues are in principle prone to succumb to ferroptosis. This knowledge will be of utmost importance when interrogating the aetiopathologies and upstream events possibly leading to ferroptosis in relevant disease scenarios, such as neuronal demise in amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), as well as in IRI in the context of organ transplantation, stroke and cardiac infarction. What remains entirely unanswered is the potential cross-talk of cells dying by ferroptosis with the immune system. Yet, it can be anticipated that similar to other immunologically non-silent forms of non-apoptotic cell death, such as necroptosis, cellular contents and factors released by ferroptotic cells may have a strong pro-inflammatory impact [101]. If so, it would be highly interesting to see if oxidatively modified lipids or its breakdown products might ignite such a pro-inflammatory auto-amplification loop [102]. The implementation of animal models in the study of ferroptosis will become even more relevant in future studies as the redox environment between (cell) culture conditions and a whole organism such as the mouse vary substantially. This is best illustrated by the fact that mice with targeted loss of SLC7A11 are fully viable [103], whereas any type of cells isolated from these knockout mice die within 24 h upon isolation. The loss of SLC7A11 can thus be easily bypassed by other transport systems in vivo as approx. half of cysteine is still present in its reduced form in plasma and extracellular compartment. By stark contrast, in tissue culture conditions virtually all cysteine is readily oxidized to cystine whereupon it can only be taken up by system xc−. This might be of utmost importance when considering novel anticancer strategies based on system xc− inhibition. The same holds true for vitamin E content (and probably selenium, iron etc.) in cell culture serum and equally important in animal diets, as vitamin E does not only prevent cells from succumbing to ferroptosis but was also shown to compensate for the conditional loss of GPX4 in endothelial cells and hepatocytes in vivo [77], [78]. Another important factor that deserves consideration is the fatty acid composition of serum, which, in light of the role of ACSL4 in ferroptosis, may also have a significant impact on the outcome in different experimental settings.