Anti-Cancer Effects of Sulfasalazine and Vitamin E Succinate in MDA-MB 231 Triple-Negative Breast Cancer Cells

Wei, Chyou Wei; Yu, Yung Luen; Lu, Ji; Hung, Yung‐Jr; Liu, Hsiao Chun; Yiang, Giou Teng

doi:10.7150/ijms.30380

Cited by 14 publications

(7 citation statements)

References 41 publications

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“…Moreover, similar effects were obtained in CSCs co-treated with either Etoposide and SSZ (Figure 2a 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 In contrast, the same treatments did not induce any significant alteration in the formation/propagation of ER-CSCs until two weeks of exposure (Figure 2b). In fact, Etoposide treatment reduced CSC propagation by 38% at four weeks, and this effect remained unchanged until six weeks of treatment (Figure 2b).…”

Section: Etoposide Prevents the Formation Of Htla-cscs After 3 Weeks Of Treatment While It Completely Counteracts The Formation Of Er-cscsupporting

confidence: 58%

“…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: 91%

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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: Etoposide Prevents the Formation Of Htla-cscs After 3 Weeks Of Treatment While It Completely Counteracts The Formation Of Er-cscsupporting

confidence: 58%

Section: Resultsmentioning

confidence: 91%

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

et al. 2021

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“…A similar effect was also demonstrated by Cobler et al in 2018, who showed that xCT inhibition sensitized breast tumours to γ-radiation via glutathione reduction [322], suggesting a synergic role of xCT inhibition and ROS-generating therapies in killing cancer cells. The anticancer activity of sulfasalazine was also confirmed by Wei et al, who showed that sulfasalazine induced cytotoxicity in MDA-MB-231 breast cancer cells, and the cytotoxicity could be abated by low-dose and enhanced by high-dose vitamin E succinate [323].…”

Section: Slc7a11 In Breast Cancermentioning

confidence: 59%

Targeting ferroptosis in breast cancer

et al. 2020

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Ferroptosis is a recently discovered distinct type of regulated cell death caused by the accumulation of lipid-based ROS. Metabolism and expression of specific genes affect the occurrence of ferroptosis, making it a promising therapeutic target to manage cancer. Here, we describe the current status of ferroptosis studies in breast cancer and trace the key regulators of ferroptosis back to previous studies. We also compare ferroptosis to common regulated cell death patterns and discuss the sensitivity to ferroptosis in different subtypes of breast cancer. We propose that viewing ferroptosis-related studies from a historical angle will accelerate the development of ferroptosis-based biomarkers and therapeutic strategies in breast cancer.

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“…xCT plays a predominant role in the System x c − ; therefore, the intracellular glutathione levels are determined by the expression and function of xCT. Accumulated evidence has demonstrated that xCT plays a crucial role in many cancers, like bladder cancer, 7 thyroid cancer, 8 triple‐negative breast cancer 9 and prostate cancer 10 . However, the role of the xCT in gastric cancer has not been well elucidated yet.…”

Section: Introductionmentioning

confidence: 99%

Sulfasalazine, a potent suppressor of gastric cancer proliferation and metastasis by inhibition of xCT: Conventional drug in new use

Zhuang

Liu

Yang

et al. 2021

J Cellular Molecular Medi

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The aim of this study was to explore the role of sulfasalazine on proliferation and metastasis in gastric cancer by inhibition of xCT. The relationships between clinical characteristics and xCT expression were analysed. An immunohistochemical staining assay and Western blot were performed among gastric cancers and normal gastric tissues. qPCR and Western blot were also used to evaluate the mRNA and protein expression in the normal gastric cell and eight gastric cancer cells, respectively. CCK‐8 and colony formation assays were used to evaluate the effect of sulfasalazine on the proliferation and colony formation ability of three gastric cancers. The effect of sulfasalazine on the migration and invasion abilities of three cancer cells was assessed by the Transwell assay. xCT protein is up‐regulated in gastric cancer specimens and cells. Three gastric cancer cells with high, medium and low expression of xCT were selected for the following analyses. CCK‐8 assays revealed that sulfasalazine could attenuate the proliferation of HGC‐27 and AGS. Also, the colony formation assay revealed that sulfasalazine might attenuate the colony formation ability in HGC‐27 and AGS cells. Plus, the Transwell assays demonstrated that sulfasalazine might attenuate the migration and invasion abilities in HGC‐27 and AGS cells. In conclusion, higher expression of xCT is associated with advanced tumour stage and poor overall survival of gastric cancer. Sulfasalazine can attenuate the proliferation, colony formation, metastasis and invasion of gastric cancer in vitro. Further study is required to validate our findings.

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Anti-Cancer Effects of Sulfasalazine and Vitamin E Succinate in MDA-MB 231 Triple-Negative Breast Cancer Cells

Cited by 14 publications

References 41 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

Targeting ferroptosis in breast cancer

Sulfasalazine, a potent suppressor of gastric cancer proliferation and metastasis by inhibition of xCT: Conventional drug in new use

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