Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma

Hassannia, Behrouz; Wiernicki, Bartosz; Ingold, Irina; Qu, Feng; Herck, Simon Van; Tyurina, Yulia Y.; Bayır, Hülya; Abhari, Behnaz Ahangarian; Angeli, José Pedro Friedmann; Choi, Sze Men; Meul, Eline; Heyninck, Karen; Declerck, Ken; Chirumamilla, Chandra Sekhar; Lahtela‐Kakkonen, Maija; Camp, Guy Van; Krysko, Dmitri V.; Ekert, Paul G.; Fulda, Simone; Geest, Bruno G. De; Conrad, Marcus; Kagan, Valerian E.; Berghe, Wim Vanden; Vandenabeele, Peter; Berghe, Tom Vanden

doi:10.1172/jci99032

Cited by 477 publications

(448 citation statements)

References 61 publications

(81 reference statements)

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“…All three treatments altered a common set of 23 genes ( Fig. 3f and Supplementary Table 2) including genes previously identified as increased during ferroptosis including RHOB, SLC2A3, DDIT4 and HMOX1 15,29 . In addition, the previously reported ferroptosis marker CHAC1 29 was commonly upregulated in both tung-oil treated tumors and αESA-treated cells.…”

Section: Conjugated Pufas Exhibit Anti-cancer Activity and Promote Exmentioning

confidence: 93%

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

Beatty

Singh

Tyurina

et al. 2019

Preprint

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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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Section: Conjugated Pufas Exhibit Anti-cancer Activity and Promote Exmentioning

confidence: 93%

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confidence: 99%

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

Beatty

Singh

Tyurina

et al. 2019

Preprint

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“…For a detailed description of class I-III FINS refer to Yang et al (240), Dixon and Stockwell (2), and Lu et al (237). Although, it is classed as type II, withaferin A, a natural ferroptosisinducing agent, increases the intracellular iron pool and inhibited growth of neuroblastoma xenografts (241). Likewise, artesunate, an anti-malarial, interacts with lysosomal iron and generates ROS leading to ferroptosis.…”

Section: Ferroptosismentioning

confidence: 99%

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

et al. 2020

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Iron is an essential nutrient that plays a complex role in cancer biology. Iron metabolism must be tightly controlled within cells. Whilst fundamental to many cellular processes and required for cell survival, excess labile iron is toxic to cells. Increased iron metabolism is associated with malignant transformation, cancer progression, drug resistance and immune evasion. Depleting intracellular iron stores, either with the use of iron chelating agents or mimicking endogenous regulation mechanisms, such as microRNAs, present attractive therapeutic opportunities, some of which are currently under clinical investigation. Alternatively, iron overload can result in a form of regulated cell death, ferroptosis, which can be activated in cancer cells presenting an alternative anti-cancer strategy. This review focuses on alterations in iron metabolism that enable cancer cells to meet metabolic demands required during different stages of tumorigenesis in relation to metastasis and immune response. The strength of current evidence is considered, gaps in knowledge are highlighted and controversies relating to the role of iron and therapeutic targeting potential are discussed. The key question we address within this review is whether iron modulation represents a useful approach for treating metastatic disease and whether it could be employed in combination with existing targeted drugs and immune-based therapies to enhance their efficacy.

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“…Ferrostatin-1 distinctly raises the GPX4 and FTH1 expression and blocks the PTGS2 and ACSL4 level [50]. In lung cancer cell lines, cell proliferation is decreased with GPX4 knockdown and this inhibition could be reversed by ferrostatin-1, the speci c inhibitor of ferroptosis [14,51]. These results further indicated that GPX4 can negatively regulate ferroptosis, and ferrostatin-1 partially reversed the effect of sh-GPX4.…”

Section: Discussionmentioning

confidence: 79%

Role of GPX4-Mediated Ferroptosis in the Sensitivity of Triple Negative Breast Cancer Cells to Gefitinib

Song

Wang

Liu

et al. 2020

Preprint

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Background: Gefitinib exhibits antitumor activity in the patients with breast cancer, but the resistance to gefitinib in triple negative breast cancer (TNBC) is a new concern. Glutathione peroxidase 4 (GPX4) is a leading regulator of ferroptosis, which is of importance for the survival of TNBC cells. This study investigated GPX4-mediated ferroptosis in gefitinib sensitivity in TNBC.Methods: Gefitinib resistant TNBC cells MDA-MB-231/Gef and HS578T/Gef were constructed, and treated with lentivirus sh-GPX4 and ferroptosis inhibitor ferrostatin-1. GPX4 expression, cell viability and apoptosis were detected. Malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS) levels were evaluated. The levels of ferroptosis-related proteins ACSL4, PTGS2, NOX1 and FTH1 were detected. Subcutaneous tumor model was established in nude mice, and gefitinib was intraperitoneally injected. Apoptosis was detected by TUNEL staining and Ki-67 expression was detected by immunohistochemistry.Results: GPX4 was increased in gefitinib-resistant cells. After silencing GPX4, the inhibition rate of cell viability increased, the limitation of colony formation ability reduced, apoptosis rate increased, and the sensitivity of cells to gefitinib was improved. After silencing GPX4, MDA level and ROS production were significantly increased, while GSH level was decreased. Silencing GPX4 promoted ferroptosis. After inhibition of ferroptosis by ferrostatin-1, it revealed that inhibition of GPX4 promoted gefitinib sensitivity by promoting cell ferroptosis. In vivo experiments also showed that inhibition of GPX4 enhanced the anticancer effect of gefitinib through promoting ferroptosis.Conclusion: Inhibition of GPX4 stimulated ferroptosis and thus enhanced TNBC cell sensitivity to gefitinib.

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Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma

Cited by 477 publications

References 61 publications

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

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

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

Role of GPX4-Mediated Ferroptosis in the Sensitivity of Triple Negative Breast Cancer Cells to Gefitinib

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