FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation

Gaschler, Michael M.; Andia, Alexander A.; Liu, Hengrui; Csuka, J.; Hurlocker, Brisa; Vaiana, Christopher A.; Heindel, Daniel W.; Zuckerman, Dylan S.; Bos, Pieter H.; Reznik, Eduard; Ye, Lingplak; Tyurina, Yulia Y.; Lin, Alex T.L.; Shchepinov, Mikhail S.; Chan, Amy; Peguero-Pereira, Eveliz; Fomich, Maksim A.; Daniels, Jacob D.; Bekish, Andrei V.; Shmanai, Vadim V.; Kagan, Valerian E.; Mahal, Lara K.; Woerpel, K. A.; Stockwell, Brent R.

doi:10.1038/s41589-018-0031-6

Cited by 562 publications

(375 citation statements)

References 54 publications

(76 reference statements)

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“…Due to the iron‐dependent feature of FINO2 and the increased iron level in malignant cells, FINO2 is more potent in malignant cells compared with nonmalignant cells of the same tissue. Studies on the two enantiomers of FINO2 have shown that (−)‐FINO2 is more active and selective toward cancerous fibroblasts than (+)‐FINO2 . Moreover, in vitro experiments showed that chemoresistance‐related pathways (e.g., p53 mutation, BCL‐2 overexpression) can be bypassed by FINO2 (Figure H) …”

Section: Ferroptosis Inducers For Cancer Therapymentioning

confidence: 99%

Recent Progress in Ferroptosis Inducers for Cancer Therapy

et al. 2019

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Ferroptosis is a newly discovered form of regulated cell death that is the nexus between metabolism, redox biology, and human health. Emerging evidence shows the potential of triggering ferroptosis for cancer therapy, particularly for eradicating aggressive malignancies that are resistant to traditional therapies. Recently, there has been a great deal of effort to design and develop anticancer drugs based on ferroptosis induction. Recent advances of ferroptosis‐inducing agents at the intersection of chemistry, materials science, and cancer biology are presented. The basis of ferroptosis is summarized first to highlight the feasibility and characteristics of triggering ferroptosis for cancer therapy. A literature review of ferroptosis inducers (including small molecules and nanomaterials) is then presented to delineate their design, action mechanisms, and anticancer applications. Finally, some considerations for research on ferroptosis inducers are spotlighted, followed by a discussion on the challenges and future development directions of this burgeoning field.

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Section: Ferroptosis Inducers For Cancer Therapymentioning

confidence: 99%

Recent Progress in Ferroptosis Inducers for Cancer Therapy

et al. 2019

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“…By contrast, 1 S ,3 R ‐RSL3 (hereafter RSL3), and related molecules, covalently inactivate GPX4 by binding to the active site selenocysteine . GPX4 protein expression and/or activity can also be inhibited indirectly by the small molecules FIN56 and FINO 2 , through mechanisms that remain only partially characterized …”

Section: Introductionmentioning

confidence: 99%

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

2019

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Oxygen is necessary for aerobic metabolism but can cause the harmful oxidation of lipids and other macromolecules. Oxidation of cholesterol and phospholipids containing polyunsaturated fatty acyl chains can lead to lipid peroxidation, membrane damage, and cell death. Lipid hydroperoxides are key intermediates in the process of lipid peroxidation. The lipid hydroperoxidase glutathione peroxidase 4 (GPX4) converts lipid hydroperoxides to lipid alcohols, and this process prevents the iron (Fe2+)‐dependent formation of toxic lipid reactive oxygen species (ROS). Inhibition of GPX4 function leads to lipid peroxidation and can result in the induction of ferroptosis, an iron‐dependent, non‐apoptotic form of cell death. This review describes the formation of reactive lipid species, the function of GPX4 in preventing oxidative lipid damage, and the link between GPX4 dysfunction, lipid oxidation, and the induction of ferroptosis.

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“…The central ferroptotic regulator is glutathione peroxidase 4 (GPX4), which is the only known peroxidase capable of efficiently reducing esterified, oxidized fatty acids into unreactive alcohols 7 . Small molecules that trigger ferroptosis identified thus far include agents that inhibit GPX4 directly, molecules that deplete the GPX4 cofactor glutathione, and compounds that oxidize iron, all of which lead to lipid hydroperoxide accumulation 1,8 . Elevated lipid hydroperoxides lead to disruption of membrane architecture, production of reactive aldehydes, and ultimately cell death 9 .…”

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Conjugated linolenic fatty acids trigger ferroptosis in triple-negative breast cancer

Beatty

Singh

Tyurina

et al. 2019

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Recent studies have shown that cancer cells, including renal cell carcinoma, melanoma and glioblastoma are vulnerable to ferroptosis [10][11][12][13][14][15][16] . Furthermore therapy-resistant mesenchymal cancer cells exhibit a greater reliance on GPX4 activity for survival 10,17 . These findings have highlighted the therapeutic potential of pro-ferroptotic agents, but it remains unclear whether induction of ferroptosis can be used therapeutically to selectively kill cancer cells in vivo 1 . A major challenge to testing this hypothesis has been the absence of selective ferroptosis-inducing agents, such as GPX4 inhibitors, suitable for use in vivo 18 .While suppressing the GPX4-mediated antioxidant response is one approach to induce ferroptosis, a complementary approach is to promote the production of lipid hydroperoxides by increasing the availability of their PUFA precursors. Hydroperoxides can spread by a free radical-mediated chain reaction leading to oxidation of adjacent PUFAs, and consequently higher PUFA levels could increase vulnerability to the propagation of lipid peroxides. Indeed, supplementation of cells with the PUFA arachidonic acid sensitizes them to ferroptosis triggered by GPX4 inhibitors 19 . Importantly, this approach to enhancing ferroptosis would exploit the propensity of cancer cells to scavenge fatty acids from their environment 20 .Here we report a vulnerability in triple-negative breast cancer (TNBC) to ferroptosis associated with the accumulation of PUFAs, and identified conjugated linolenic fatty acids as PUFAs that induce ferroptosis.Mechanistically, accumulation of PUFAs in TNBC triggered ferroptosis by a mode of action distinct from canonical ferroptosis inducers. We show that oral administration of tung nut oil, naturally rich in the conjugated PUFA α-eleostearate, has anti-cancer activity in a xenograft model of TNBC. α-Eleostearate metabolites could be detected in tumors of treated mice and was associated with expression of ferroptotic markers. These results introduce a distinct class of ferroptosis inducers and offer novel insights into the molecular basis of ferroptotic sensitivity. The tractability of these dietary, pro-ferroptotic fatty acids addresses the current lack of effective GPX4 inhibitors for use in vivo and suggests a novel opportunity to exploit a metabolic liability in an aggressive breast cancer subtype.

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FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation

Cited by 562 publications

References 54 publications

Recent Progress in Ferroptosis Inducers for Cancer Therapy

Recent Progress in Ferroptosis Inducers for Cancer Therapy

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

Conjugated linolenic fatty acids trigger ferroptosis in triple-negative breast cancer

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