Phenazine derivatives attenuate the stemness of breast cancer cells through triggering ferroptosis

Yang, Yue; Lu, Yuanyuan; Zhang, Chunhua; Guo, Qianqian; Zhang, Wenzhou; Wang, Ting; Xia, Zhuolu; Liu, Jing; Cheng, Xiuyan; Xi, Tao; Jiang, Feng; Zheng, Lufeng

doi:10.1007/s00018-022-04384-1

Cited by 24 publications

(19 citation statements)

References 54 publications

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“…The detailed procedure was referred to in our previous study . Briefly, when cell confluence reached 90% at 6-well plates, a wound was produced on cell surface, and cell fragments were washed out with PBS twice.…”

Section: Methodsmentioning

confidence: 99%

“…The detailed procedure was referred to in our previous study. 39 Briefly, when cell confluence reached 90% at 6-well plates, a wound was produced on cell surface, and cell fragments were washed out with PBS twice. To exclude the effects of cell proliferation on cell migration ability, cells were then cultured in serum-starved medium (≤2%) containing compounds or solvent.…”

Section: N′-hydroxy-n-(4-ethylphenyl)-formamidamide (31b)mentioning

confidence: 99%

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Identification of a Novel Potent CYP4Z1 Inhibitor Attenuating the Stemness of Breast Cancer Cells through Lead Optimization

et al. 2022

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Pharmacological targeting cancer stem cells are emerging as a novel therapeutic modality for cancer treatment and prevention. Human cytochrome P450 enzyme CYP4Z1 represents a promising target for its potential role in attenuating the stemness of breast cancer cells. In order to develop potent and selective CYP4Z1 inhibitors, a series of novel N-hydroxyphenylformamidines were rationally designed and synthesized from a pan-CYP inhibitor HET0016. CYP4Z1 inhibitory activities of the newly synthesized derivatives were evaluated, and the structure–activity relationships (SARs) were summarized. Among them, compound 7c exhibited the best inhibitory activity with an IC50 value of 41.8 nM. Furthermore, it was found that 7c decreased the expression of stemness markers, spheroid formation, and metastatic ability as well as tumor-initiation capability in a concentration-dependent manner in vitro and in vivo. Altogether, compound 7c might be a potential lead compound to develop CYP4Z1 inhibitor with more favorable druggability for clinical application to treat breast cancer.

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Section: Methodsmentioning

confidence: 99%

Section: N′-hydroxy-n-(4-ethylphenyl)-formamidamide (31b)mentioning

confidence: 99%

Identification of a Novel Potent CYP4Z1 Inhibitor Attenuating the Stemness of Breast Cancer Cells through Lead Optimization

et al. 2022

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“…Furthermore, CSCs have been found to have immunomodulatory activity as CSCs have been shown to exhibit the immunotherapeutic resistance. According to these characteristics, CSCs play an irreplaceable role in the treatment of malignant tumors as our previous studies have shown targeting CSCs can significantly suppress tumor migration, invasion, and drug resistance [32][33][34]. Epigenetics plays an important role in maintaining the above biological characteristics of CSCs, which refers to the phenomenon that the DNA sequence has not changed but the traits have heritable changes.…”

Section: The Effects Of M 6 A-rna Modification On Csc Progressionmentioning

confidence: 99%

The roles of m6A RNA methylation modification in cancer stem cells: new opportunities for cancer suppression

Chen

Shi

et al. 2022

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As a reversible post-transcriptional modification, N6-methyladeno sine is the most common form of RNA modification in eukaryotic mRNA. Cancer stem cells (CSCs), which are a subpopulation of cells with self-renewal ability and differentiation potential, have been regarded to be one of the roots of tumor occurrence, recurrence, and metastasis. Currently, numerous studies have demonstrated that m6A RNA modification is critically implicated in the regulation of CSCs stemness or the CSC-like traits of cancer cells. This review summarized the effects of m6A RNA modification-related enzymes and underlying mechanisms contributing to CSCs or cancer cell stemness, which may provide novel targets and research directions for the specifical elimination of CSCs or cancer cells with stemness.

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“…Recently, based on the strategy of molecular hybridization, our group successfully screened out pyran‐phenazine hybrid molecules CPUL129 and CPUL149 ( Figure 1) from the phenazine library established by us before [11–18] . These compounds could accumulate and sequester iron in lysosomes through interacting with iron and regulating the expression of proteins (IRP2, TfR1, ferritin) engaged in iron transport and strorage, eventually specifically inhibit the stemness of breast cancer cells through triggering ferroptosis [19] …”

Section: Introductionmentioning

confidence: 99%

“…[11 -18] These compounds could accumulate and sequester iron in lysosomes through interacting with iron and regulating the expression of proteins (IRP2, TfR1, ferritin) engaged in iron transport and strorage, eventually specifically inhibit the stemness of breast cancer cells through triggering ferroptosis. [19] Inspired by the α,β-unsaturated ketone structure of CPUL129 and CPUL149, we kept trying to splice phenazine and chalcone containing α,β-unsaturated ketone, so we designed different linkers to couple phenazine and chalcone pharmacophores to continue the investigation of phenazine analogs triggering ferroptosis as potential anticancer drug. Specifically, we used the CuAAC reaction known as click chemistry, an important medicinal chemistry method, as well as simple etherification reaction to construct thirty-seven novel chalcone-phenazine hybrids C1 ~C13 and F1 F24 with 1,2,3-triazole and ethyl group as linkers, respectively.…”

Section: Introductionmentioning

confidence: 99%

Novel Chalcone‐Phenazine Hybrids Induced Ferroptosis in U87‐MG Cells through Activating Ferritinophagy

Zhang

Ding

Xia

et al. 2023

Chemistry & Biodiversity

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Thirty-seven novel chalcone-phenazine hybrid molecules (C1 ~C13 and F1 ~F24) with 1,2,3-triazole or ethyl group as linkers were designed and synthesized in this study. Some compounds exhibited selective cytotoxicity against U87-MG cancer cell lines in vitro, in which compound C4 were found to have the best antiproliferative activity. SAR study indicated 1,2,3-triazole group may be crucial for enhancing compounds' cytotoxicity. C4 was verified to induce ferroptosis in U87-MG cells by transcription, lipid peroxidation, lipid ROS assays. Furthermore, C4 was up-regulated LC3-II, degradated FTH1, and then increasing iron resulted in the down-regulation of NCOA4. Together, all above evidences highlighted the potential of compound C4 that triggered ferroptosis by activating ferritinophagy against U87-MG cells.

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Phenazine derivatives attenuate the stemness of breast cancer cells through triggering ferroptosis

Cited by 24 publications

References 54 publications

Identification of a Novel Potent CYP4Z1 Inhibitor Attenuating the Stemness of Breast Cancer Cells through Lead Optimization

Identification of a Novel Potent CYP4Z1 Inhibitor Attenuating the Stemness of Breast Cancer Cells through Lead Optimization

The roles of m6A RNA methylation modification in cancer stem cells: new opportunities for cancer suppression

Novel Chalcone‐Phenazine Hybrids Induced Ferroptosis in U87‐MG Cells through Activating Ferritinophagy

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