The Xc− inhibitor sulfasalazine improves the anti-cancer effect of pharmacological vitamin C in prostate cancer cells via a glutathione-dependent mechanism

Zheng, Zijie; Luo, Ganhua; Shi, Xiulin; Long, Ya‐Qiu; Shen, Wanqing; Li, Zhoulei; Zhang, Xiangsong

doi:10.1007/s13402-019-00474-8

Cited by 28 publications

(19 citation statements)

References 51 publications

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“…Together these results demonstrate that ER-CSCs maintain their resistance to Etoposide and show that ER-CSC generation is totally inhibited by co-treatments with SSZ or C2-4. Moreover, the data obtained confirm that the inhibition of xCT is a useful strategy for enhancing the effect of chemotherapy [ 37 , 38 , 39 , 40 , 41 , 42 ] and, although the use of SSZ is limited due to its low bioavailability, its employment has been recently considered to treat high risk NB [ 43 ]. In addition, the results obtained in C2-4-co-treated cells suggest that the inhibition of PKCα could be a novel way to sensitize CSCs to therapy by sustaining GSH depletion.…”

Section: Resultsmentioning

confidence: 90%

PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating Ferroptosis

et al. 2021

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Cancer stem cells (CSCs) are a limited cell population inside a tumor bulk characterized by high levels of glutathione (GSH), the most important antioxidant thiol of which cysteine is the limiting amino acid for GSH biosynthesis. In fact, CSCs over-express xCT, a cystine transporter stabilized on cell membrane through interaction with CD44, a stemness marker whose expression is modulated by protein kinase Cα (PKCα). Since many chemotherapeutic drugs, such as Etoposide, exert their cytotoxic action by increasing reactive oxygen species (ROS) production, the presence of high antioxidant defenses confers to CSCs a crucial role in chemoresistance. In this study, Etoposide-sensitive and -resistant neuroblastoma CSCs were chronically treated with Etoposide, given alone or in combination with Sulfasalazine (SSZ) or with an inhibitor of PKCα (C2-4), which target xCT directly or indirectly, respectively. Both combined approaches are able to sensitize CSCs to Etoposide by decreasing intracellular GSH levels, inducing a metabolic switch from OXPHOS to aerobic glycolysis, down-regulating glutathione-peroxidase-4 activity and stimulating lipid peroxidation, thus leading to ferroptosis. Our results suggest, for the first time, that PKCα inhibition inducing ferroptosis might be a useful strategy with which to fight CSC chemoresistance.

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Section: Resultsmentioning

confidence: 90%

PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating Ferroptosis

et al. 2021

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“…GS expression was analyzed after microPET/CT imaging. The immunohistochemical staining was carried out according to the previously described procedures ( He et al, 2016 ; Zheng et al, 2020 ). Positive rate of Ki-67 was analyzed using Image-pro plus 6.0 (Media Cybernetics, United States).…”

Section: Methodsmentioning

confidence: 99%

Pharmacological Vitamin C Treatment Impedes the Growth of Endogenous Glutamine-Dependent Cancers by Targeting Glutamine Synthetase

et al. 2021

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Purpose: Glutamine synthetase (GS) is the only currently known enzyme responsible for synthesizing endogenous glutamine (Gln). GS exerts a critical role in the oncogenesis of endogenous Gln-dependent cancers, making it an attractive target for anti-tumor therapies. A mixed-function oxidation system consisting of vitamin C (VC), oxygen, and trace metals can oxidize GS and promote its degradation. The current study aims to explore the effect of pharmacological VC treatment on GS.Methods: Endogenous Gln-dependent cancer lines (breast cancer MCF7 and prostate cancer PC3) were selected to establish chronic Gln-deprived MCF7 and PC3 cell models. The expression of GS in parental and chronic Gln-deprived tumor cells exposed to VC treatment and control was determined by Western blot analysis. The anti-cancer effects of VC on parental and chronic Gln-deprived tumor cells were assessed by CCK-8 and annexin V-FITC/PI FACS assays. In addition, changes in cellular reactive oxygen species (ROS), glutathione (GSH) levels and NADPH/NADP + ratio were analyzed to explore the underlying mechanisms. Moreover, BALB/c nude mice xenografting with parental and chronic Gln-deprived prostate cancer cells were constructed to evaluate the in vivo therapeutic effect of VC. Finally, tumor 13N-ammonia uptake in mice bearing prostate cancer xenografts was analyzed following treatment with VC and the expression of GS in xenografts were detected by immunohistochemistry.Results: Cells overexpressing GS were obtained by chronic Gln deprivation. We found that the cytotoxic effect of VC on cancer cells was positively correlated with the expression of GS. Additionally, VC treatment led to a significant increase in ROS production, as well as GSH depletion and NADPH/NADP + reduction. These changes could be reversed by the antioxidant N-acetyl-L-cysteine (NAC). Furthermore, pharmacological VC treatment exhibited a more significant therapeutic effect on xenografts of prostate cancer cells overexpressing GS, that could be well monitored by 13N-ammonia PET/CT imaging.Conclusion: Our findings indicate that VC can kill cancer cells by targeting glutamine synthetase to induce oxidative stress. VC could be used as an anti-cancer treatment for endogenous glutamine-dependent cancers.

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“…Sulfasalazine blocks the cystine–glutamate exchange transporter XCT that has also been found to be overexpressed in tumor cells [ 137 ]. Sulfasalazine is currently being tested in various tumor models, showing promising results in enhancing tumor clearance in prostate cancer [ 138 , 139 ]. Combined blockage of metabolite transporters in tumor cells may thus offer a new strategy for cancer therapy.…”

Section: Metabolite Transport As Therapeutic Targetmentioning

confidence: 99%

Metabolite Transporters as Regulators of Immunity

Weiss

Angiari

2020

Metabolites

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In the past decade, the rise of immunometabolism has fundamentally reshaped the face of immunology. As the functions and properties of many (immuno)metabolites have now been well described, their exchange among cells and their environment have only recently sparked the interest of immunologists. While many metabolites bind specific receptors to induce signaling cascades, some are actively exchanged between cells to communicate, or induce metabolic reprograming. In this review, we give an overview about how active metabolite transport impacts immune cell function and shapes immunological responses. We present some examples of how specific transporters feed into metabolic pathways and initiate intracellular signaling events in immune cells. In particular, we focus on the role of metabolite transporters in the activation and effector functions of T cells and macrophages, as prototype adaptive and innate immune cell populations.

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The Xc− inhibitor sulfasalazine improves the anti-cancer effect of pharmacological vitamin C in prostate cancer cells via a glutathione-dependent mechanism

Cited by 28 publications

References 51 publications

PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating Ferroptosis

PKCα Inhibition as a Strategy to Sensitize Neuroblastoma Stem Cells to Etoposide by Stimulating Ferroptosis

Pharmacological Vitamin C Treatment Impedes the Growth of Endogenous Glutamine-Dependent Cancers by Targeting Glutamine Synthetase

Metabolite Transporters as Regulators of Immunity

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