Sulfasalazine-Induced Reduction of Glutathione Levels in Breast Cancer Cells: Enhancement of Growth-Inhibitory Activity of Doxorubicin

Narang, Vishal S.; Pauletti, Giovanni M.; Gout, Peter W.; Buckley, Donna J.; Buckley, Arthur R.

doi:10.1159/000100812

Cited by 73 publications

(48 citation statements)

References 56 publications

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“…This fits with the observation that CSC are chemo-resistant (2), and may reflect the increased expression of xCT in tumorspheres. In this regard, it has been demonstrated that xCT inhibition promotes the sensitization of tumor cells to doxorubicin (49,50). In accordance with these findings, we have observed that a combination of anti-xCT vaccination and doxorubicin strongly enhanced the antimetastatic potential of the individual treatments.…”

Section: Discussionsupporting

confidence: 89%

Immunotargeting of Antigen xCT Attenuates Stem-like Cell Behavior and Metastatic Progression in Breast Cancer

Lanzardo

Conti

Rooke³

et al. 2016

Cancer Research

138

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Resistance to therapy and lack of curative treatments for metastatic breast cancer suggest that current therapies may be missing the subpopulation of chemoresistant and radioresistant cancer stem cells (CSC). The ultimate success of any treatment may well rest on CSC eradication, but specific anti-CSC therapies are still limited. A comparison of the transcriptional profiles of murine Her2 þ breast tumor TUBO cells and their derived CSC-enriched tumorspheres has identified xCT, the functional subunit of the cystine/glutamate antiporter system x c À , as a surface protein that is upregulated specifically in tumorspheres. We validated this finding by cytofluorimetric analysis and immunofluorescence in TUBO-derived tumorspheres and in a panel of mouse and human triple negative breast cancer cell-derived tumorspheres. We further show that downregulation of xCT impaired tumorsphere generation and altered CSC intracellular redox balance in vitro, suggesting that xCT plays a functional role in CSC biology. DNA vaccination based immunotargeting of xCT in mice challenged with syngeneic tumorsphere-derived cells delayed established subcutaneous tumor growth and strongly impaired pulmonary metastasis formation by generating anti-xCT antibodies able to alter CSC self-renewal and redox balance. Finally, anti-xCT vaccination increased CSC chemosensitivity to doxorubicin in vivo, indicating that xCT immunotargeting may be an effective adjuvant to chemotherapy. Cancer Res; 76(1); 62-72. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 89%

Immunotargeting of Antigen xCT Attenuates Stem-like Cell Behavior and Metastatic Progression in Breast Cancer

Lanzardo

Conti

Rooke³

et al. 2016

Cancer Research

138

View full text Add to dashboard Cite

show abstract

“…*P < 0.05, **P < 0.01, ***P < 0.001 vs. NTC Pac (-); # P < 0.05, ## P < 0. SSA or BSO, respectively, potentiates the anticancer effect of chemotherapy on breast cancer cell lines (38,39). Our results demonstrate that targeting the glutathione synthesis pathway also decreases the number of BCSCs, which are required for breast cancer recurrence and metastasis.…”

Section: Discussionmentioning

confidence: 61%

Chemotherapy triggers HIF-1–dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype

Samanta

Xiang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

223

205

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Triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancer but is responsible for a disproportionate share of morbidity and mortality because of its aggressive characteristics and lack of targeted therapies. Chemotherapy induces enrichment of breast cancer stem cells (BCSCs), which are responsible for tumor recurrence and metastasis. Here, we demonstrate that chemotherapy induces the expression of the cystine transporter xCT and the regulatory subunit of glutamate-cysteine ligase (GCLM) in a hypoxia-inducible factor (HIF)-1-dependent manner, leading to increased intracellular glutathione levels, which inhibit mitogenactivated protein kinase kinase (MEK) activity through copper chelation. Loss of MEK-ERK signaling causes FoxO3 nuclear translocation and transcriptional activation of the gene encoding the pluripotency factor Nanog, which is required for enrichment of BCSCs. Inhibition of xCT, GCLM, FoxO3, or Nanog blocks chemotherapy-induced enrichment of BCSCs and impairs tumor initiation. These results suggest that, in combination with chemotherapy, targeting BCSCs by inhibiting HIF-1-regulated glutathione synthesis may improve outcome in TNBC.hypoxia-inducible factor | paclitaxel | pluripotency factors | chemotherapy resistance | tumor-initiating cells

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“…The x c À transporter has been shown in various cancers to supply cells with cystine for GSH synthesis resulting in increased proliferation and GSH-related drug resistance (Doxsee et al, 2007;Narang et al, 2007). The goal of this study was to investigate whether a similar x c À -mediated system was also used by pancreatic cancer cells for growth, survival and drug-related resistance.…”

Section: Discussionmentioning

confidence: 99%

The xc− cystine/glutamate antiporter: a mediator of pancreatic cancer growth with a role in drug resistance

et al. 2008

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The x c − cystine transporter enhances biosynthesis of glutathione, a tripeptide thiol important in drug resistance and cellular defense against oxidative stress, by enabling cellular uptake of cystine, a rate-limiting precursor. Because it is known to regulate glutathione levels and growth of various cancer cell types, and is expressed in the pancreas, we postulate that it is involved in growth and drug resistance of pancreatic cancer. To examine this, we characterised expression of the x c − transporter in pancreatic cancer cell lines, MIA PaCa-2, PANC-1 and BxPC-3, as subjected to cystine-depletion and oxidative stress. The results indicate that these cell lines depend on x c − -mediated cystine uptake for growth, as well as survival in oxidative stress conditions, and can modulate x c − expression to accommodate growth needs. Immunohistochemical analysis showed that the transporter was differentially expressed in normal pancreatic tissues and overexpressed in pancreatic cancer tissues from two patients. Furthermore, gemcitabine resistance of cells was associated with elevated x c − expression and specific x c − inhibition by monosodium glutamate led to growth arrest. The results suggest that the x c − transporter by enhancing glutathione biosynthesis plays a major role in pancreatic cancer growth, therapy resistance and represents a potential therapeutic target for the disease.

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Sulfasalazine-Induced Reduction of Glutathione Levels in Breast Cancer Cells: Enhancement of Growth-Inhibitory Activity of Doxorubicin

Cited by 73 publications

References 56 publications

Immunotargeting of Antigen xCT Attenuates Stem-like Cell Behavior and Metastatic Progression in Breast Cancer

Immunotargeting of Antigen xCT Attenuates Stem-like Cell Behavior and Metastatic Progression in Breast Cancer

Chemotherapy triggers HIF-1–dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype

The xc− cystine/glutamate antiporter: a mediator of pancreatic cancer growth with a role in drug resistance

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