Ethacrynic acid exhibits selective toxicity to chronic lymphocytic leukemia cells by inhibition of the Wnt/beta-catenin pathway.
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Lu D, Liu JX, Endo T, Zhou H, Yao S, Willert K, Schmidt-Wolf IG, Kipps TJ, Carson DA
Ethacrynic acid exhibits selective toxicity to chronic lymphocytic leukemia cells by inhibition of the Wnt/beta-catenin pathway.
PLoS One. 2009 Dec 14;4(12):e8294. doi: 10.1371/journal.pone.0008294.
- PubMed ID
- 20011538 [ View in PubMed]
- Abstract
BACKGROUND: Aberrant activation of Wnt/beta-catenin signaling promotes the development of several cancers. It has been demonstrated that the Wnt signaling pathway is activated in chronic lymphocytic leukemia (CLL) cells, and that uncontrolled Wnt/beta-catenin signaling may contribute to the defect in apoptosis that characterizes this malignancy. Thus, the Wnt signaling pathway is an attractive candidate for developing targeted therapies for CLL. METHODOLOGY/PRINCIPAL FINDINGS: The diuretic agent ethacrynic acid (EA) was identified as a Wnt inhibitor using a cell-based Wnt reporter assay. In vitro assays further confirmed the inhibitory effect of EA on Wnt/beta-catenin signaling. Cell viability assays showed that EA selectively induced cell death in primary CLL cells. Exposure of CLL cells to EA decreased the expression of Wnt/beta-catenin target genes, including LEF-1, cyclin D1 and fibronectin. Immune co-precipitation experiments demonstrated that EA could directly bind to LEF-1 protein and destabilize the LEF-1/beta-catenin complex. N-acetyl-L-cysteine (NAC), which can react with the alpha, beta-unsaturated ketone in EA, but not other anti-oxidants, prevented the drug's inhibition of Wnt/beta-catenin activation and its ability to induce apoptosis in CLL cells. CONCLUSIONS/SIGNIFICANCE: Our studies indicate that EA selectively suppresses CLL survival due to inhibition of Wnt/beta-catenin signaling. Antagonizing Wnt signaling in CLL with EA or related drugs may represent an effective treatment of this disease.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Etacrynic acid Lymphoid enhancer-binding factor 1 Protein Humans UnknownNot Available Details - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Etacrynic acid Approved Investigational CCND1 595 downregulated Ethacrynic Acid results in decreased expression of CCND1 mRNA 11q13.3 Etacrynic acid Approved Investigational FN1 2335 downregulated Ethacrynic Acid results in decreased expression of FN1 mRNA 2q35 Etacrynic acid Approved Investigational FZD5 7855 upregulated Ethacrynic Acid results in increased expression of FZD5 mRNA 2q33.3 Etacrynic acid Approved Investigational LEF1 51176 downregulated Ethacrynic Acid results in decreased expression of LEF1 mRNA 4q25