ArticleCancer medicine2016
Dual pharmacological inhibition of glutathione and thioredoxin systems synergizes to kill colorectal carcinoma stem cells.
Article in Cancer medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 33 citations in OpenAlex.
- Unveiling the Role of GlutathioneACS pharmacology & translational science · 2026Review
- The Role of Oxidative Stress and Redox Regulation in Cancer.Cancer treatment and research · 2026Review
- [Multi-omics analysis of the relationship between oxidative stress-related gene and prostate cancer].Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences · 2025Article
- The Pentose Phosphate Pathway: From Mechanisms to Implications for Gastrointestinal Cancers.International journal of molecular sciences · 2025Review
- Colorectal Cancer Stem Cells and Targeted Agents.Pharmaceutics · 2023Review
- Targeting GSTP1 as Therapeutic Strategy against Lung Adenocarcinoma Stemness and Resistance to Tyrosine Kinase Inhibitors.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Revisiting therapeutic strategies for ovarian cancer by focusing on redox homeostasis.Oncology letters · 2022Review
- Emerging agents that target signaling pathways to eradicate colorectal cancer stem cells.Cancer communications (London, England) · 2021Review
- Glutathione S-Transferases in Cancer.Antioxidants (Basel, Switzerland) · 2021Review
- Potential Role of GST-BioMed research international · 2021Article
- Combination of Auranofin and ICG-001 Suppress the Proliferation and Metastasis of Colon Cancer.Frontiers in oncology · 2021Article
- Glutathione metabolism is essential for self-renewal and chemoresistance of pancreatic cancer stem cells.World journal of stem cells · 2020Article
- Review
- Cancer-associated fibroblasts show heterogeneous gene expression and induce vascular endothelial growth factor A (Annals of gastroenterological surgery · 2019Article
- Review
- Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells.Frontiers in pharmacology · 2019Review
- New Challenges to Study Heterogeneity in Cancer Redox Metabolism.Frontiers in cell and developmental biology · 2017Review
- Dual pharmacological inhibition of glutathione and thioredoxin systems synergizes to kill colorectal carcinoma stem cells.Cancer medicine · 2016Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
NRF2 stabilizes redox potential through genes for glutathione and thioredoxin antioxidant systems. Whether blockade of glutathione and thioredoxin is useful in eliminating cancer stem cells remain unknown. We used xenografts derived from colorectal carcinoma patients to investigate the pharmacological inhibition of glutathione and thioredoxin systems. Higher expression of five glutathione S-transferase isoforms (GSTA1, A2, M4, O2, and P1) was observed in xenograft-derived spheroids than in fibroblasts. Piperlongumine (2.5-10 μmol/L) and auranofin (0.25-4 μmol/L) were used to inhibit glutathione S-transferase π and thioredoxin reductase, respectively. Piperlongumine or auranofin alone up-regulated the expression of NRF2 target genes, but not TP53 targets. While piperlongumine showed modest cancer-specific cell killing (IC50 difference between cancer spheroids and fibroblasts: P = 0.052), auranofin appeared more toxic to fibroblasts (IC50 difference between cancer spheroids and fibroblasts: P = 0.002). The synergism of dual inhibition was evaluated by determining the Combination Index, based on the number of surviving cells with combination treatments. Molar ratios indicated synergism in cancer spheroids, but not in fibroblasts: (auranofin:piperlongumine) = 2:5, 1:5, 1:10, and 1:20. Cancer-specific cell killing was achieved at the following drug concentrations (auranofin:piperlongumine): 0.25:2.5 μmol/L, 0.5:2.5 μmol/L, or 0.25:5 μmol/L. The dual inhibition successfully decreased CD44v9 surface presentation and delayed tumor emergence in nude mouse. However, a small subpopulation persistently survived and accumulated phosphorylated histone H2A. Such "persisters" still retained lesser but significant tumorigenicity. Thus, dual inhibition of glutathione S-transferase π and thioredoxin reductase could be a feasible option for decreasing the tumor mass and CD44v9-positive fraction by disrupting redox regulation.
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