Itraconazole attenuates the stemness of nasopharyngeal carcinoma cells via triggering ferroptosis

Xu, Ying; Wang, Qian; Li, Xiaozhen; Chen, Yingyan; Xu, Gang

doi:10.1002/tox.23031

Cited by 36 publications

(30 citation statements)

References 34 publications

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“…F The expression of stemness markers was examined in the cells described in E. G Sphere-formation ability was evaluated in the cells depicted in E the chemotherapeutic effect [52]. Notably, the previous studies have shown that triggering ferroptosis through another pathway, that is sequestering iron in lysosomes, also can specifically kill CSCs [71,72], this is confirmed by a recent study showing that itraconazole can sequester iron in lysosome and thus trigger ferroptosis, which is essential for itraconazole-mediated attenuation on nasopharyngeal carcinoma spheroid stemness [73]. These results suggest that SLC7A11 might be a potential target for killing CSCs and these above ferroptosis inducers could be used for GC treatments, especially the chemo-resistant tumor types, although in vivo experiments are needed.…”

Section: Discussionmentioning

confidence: 81%

MiR-375 reduces the stemness of gastric cancer cells through triggering ferroptosis

et al. 2021

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Background Gastric cancer stem cells (CSCs) are the main causes of metastasis and drug resistance. We previously indicated that miR-375 can inhibit Helicobacter pylori-induced gastric carcinogenesis; here, we aim to explore the effects and mechanisms of miR-375 on gastric cancer (GC) cell stemness. Methods Lentivirus infection was used to construct GC cells with ectopic expression of miR-375. In vitro and in vivo experiments, including analysis of tumor spheroid formation, CD44+ sub-population with stemness, stemness marker expression, and tumor-initiating ability, were performed to evaluate the effects of miR-375 on the stemness of GC cells. Furthermore, microarray and bioinformatics analysis were performed to search the potential targets of miR-375 in GC cells. Luciferase reporter, RNA immunoprecipitation, and RNA-FISH assays were carried out to verify the targeting of miR-375. Subsequently, combined with tissue microarray analysis, erastin-resistant GC cells, transmission electron microscopy, a series of agonists and oxidative stress markers, the underlying mechanisms contributing to miR-375-mediated effects were explored. Results MiR-375 reduced the stemness of GC cells in vitro and in vivo. Mechanistically, SLC7A11 was identified as a direct target of miR-375 and miR-375 attenuated the stemness of GC cells mainly through triggering SLC7A11-dependent ferroptosis. Conclusion MiR-375 can trigger the ferroptosis through targeting SLC7A11, which is essential for miR-375-mediated inhibition on GC cell stemness. These results suggest that the miR-375/SLC7A11 regulatory axis could serve as a potential target to provoke the ferroptosis and thus attenuate the stemness of GC cells.

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Section: Discussionmentioning

confidence: 81%

MiR-375 reduces the stemness of gastric cancer cells through triggering ferroptosis

et al. 2021

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“…In colorectal CSCs, knockdown or inhibition of SLC7A11 significantly and specifically kills cancer cells and thus attenuates chemoresistance in CRC ( Xu et al, 2020c ). Besides, two nitroimidazoles ( Koike et al, 2020 ), itraconazole ( Xu et al, 2021 ), and dichloroacetate ( Sun et al, 2021 ) are also proven to have therapeutic potential through promoting ferroptosis in CSCs.…”

Section: Ferroptosis and Cancer Stem Cellsmentioning

confidence: 99%

Ferroptosis and Cancer: Complex Relationship and Potential Application of Exosomes

Liu

et al. 2021

Front. Cell Dev. Biol.

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Cell death induction has become popular as a novel cancer treatment. Ferroptosis, a newly discovered form of cell death, features regulated, iron-dependent accumulation of lipid hydroperoxides. Since this word “ferroptosis” was coined, numerous studies have examined the complex relationship between ferroptosis and cancer. Here, starting from the intrinsic hallmarks of cancer and cell death, we discuss the theoretical basis of cell death induction as a cancer treatment. We review various aspects of the relationship between ferroptosis and cancer, including the genetic basis, epigenetic modification, cancer stem cells, and the tumor microenvironment, to provide information and support for further research on ferroptosis. We also note that exosomes can be applied in ferroptosis-based therapy. These extracellular vesicles can deliver different molecules to modulate cancer cells and cell death pathways. Using exosomes to control ferroptosis occurring in targeted cells is promising for cancer therapy.

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“…Targeting iron metabolism using the iron nanoparticles can be used to treat cancer through ferroptosis, which has been approved by FDA [32] . Besides, inducing ferroptosis through sequenstering iron in lysosome has been con rmed to speci cally killing CSCs including BCSCs [10,20,22,23] . In this work, we found CPUL119, CPUL129 and CPUL149 could increase the content of iron in breast cancer cells accompanying with the change of iron-regulatory protein such as IRP2, TfR1 and ferritin.…”

Section: Discussionmentioning

confidence: 99%

“…Consistently, it has been shown that salinomycin and its drivatives could target BCSCs through sequestering iron in lysosomes [19][20][21] . Notably, targeting iron in lysosomes has been con rmed to killing CSCs in other tumors, such as nasopharyngeal carcinoma [22] and colorectal cancer [23] . These results amplify that sequestering iron in lysosomes is a promosing method in targeting BCSCs.…”

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confidence: 99%

Identification of A New Kind of Phenazine Compounds Attenuating The Stemness of Breast Cancer Cells Through Triggering Ferroptosis

Yang¹,

Lu²,

Zhang³

et al. 2021

Preprint

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Background: Breast cancer stem cells (BCSCs) are positively correlated with metastasis, chemoresistance and recurrence of breast cancer.Methods: The stemness were analyzed by qPCR and western blot, flow cytometry, cell spheroid formation assay, and tumor xenograft model. The cell viability was performed by MTT. The transcriptome analysis was used to evaluate the influence of these three compounds. The migration was analyzed by wound-healing assay, transwell invasion analysis, and metastasis model. The iron concentration was analyzed by fluorescence microscopy analysis. The lipid peroxidation and ROS level were analyzed by flow cytometry. The results were presented as mean ± SD, the analysis was Student’s t-test by using GraphPad Prism 5 software. P-values less than 0.05 were considered to be statistically significant. (*p < 0.05, **p < 0.01, ***p < 0.001).Results: Here, we tried to screen out small-molecule compounds targeting BCSCs from the phenazine library established by us before. We focused on the compounds without affecting cell viability and screened out three potential compounds (CPUL119, CPUL129, CPUL149) that can significantly attenuate the stemness of breast cancer cells, as evident by the decrease of stemness marker expression, CD44+/CD24- subpopulation, mammary spheroid-formation ability and tumor-initiating capacity. Additionally, these compounds suppressed the metastatic ability of breast cancer cells in vitro and in vivo. Combined with the transcriptome-sequencing analysis in breast cancer cells with or without the treatment of these three compounds, respectively, it was found that ferroptosis was shown on the top of the most upregulated pathways by CPUL119, CPUL129 and CPUL149. Mechanistically, we found that CPUL119, CPUL129 and CPUL149 could trigger ferroptosis by accumulating and sequestering iron in lysosomes through interacting with iron, and by regulating the expression of proteins (IRP2, TfR1, ferritin) engaged in modulating iron transport and storage. Furthermore, inhibition of ferroptosis rescued the suppression of these three compounds on the stemness of breast cancer cells. Conclusions: This study suggests that CPUL119, CPUL129 and CPUL149 can specifically inhibit the stemness of breast cancer cells through ferroptosis and may be the potential compounds for breast cancer treatment.

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Itraconazole attenuates the stemness of nasopharyngeal carcinoma cells via triggering ferroptosis

Cited by 36 publications

References 34 publications

MiR-375 reduces the stemness of gastric cancer cells through triggering ferroptosis

MiR-375 reduces the stemness of gastric cancer cells through triggering ferroptosis

Ferroptosis and Cancer: Complex Relationship and Potential Application of Exosomes

Identification of A New Kind of Phenazine Compounds Attenuating The Stemness of Breast Cancer Cells Through Triggering Ferroptosis

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