Back to Search
Start Over
Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer.
- Source :
-
Oncotarget [Oncotarget] 2016 Sep 06; Vol. 7 (36), pp. 58038-58050. - Publication Year :
- 2016
-
Abstract
- Prolonged treatment of breast cancer with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often results in acquired resistance and a narrow therapeutic index. One strategy to improve the therapeutic effects of EGFR TKIs is to combine them with drugs used for other clinical indications. Ethacrynic acid (EA) is an FDA approved drug that may have antitumor effects and may enhance the cytotoxicity of chemotherapeutic agents by binding to glutathione and inhibiting WNT signaling. While the α,β-unsaturated-keto structure of EA is similar to that of irreversible TKIs, the mechanism of action of EA when combined with irreversible EGFR TKIs in breast cancer remains unknown. We therefore investigated the combination of irreversible EGFR TKIs and EA. We found that irreversible EGFR TKIs and EA synergistically inhibit breast cancer both in vitro and in vivo. The combination of EGFR TKIs and EA induces necrosis and cell cycle arrest and represses WNT/β-catenin signaling as well as MAPK-ERK1/2 signaling. We conclude that EA synergistically enhances the antitumor effects of irreversible EGFR TKIs in breast cancer.<br />Competing Interests: The authors declare no competing financial interests.
- Subjects :
- Afatinib
Animals
Antineoplastic Agents therapeutic use
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Apoptosis drug effects
Breast pathology
Breast Neoplasms pathology
Cell Cycle Checkpoints drug effects
Cell Proliferation drug effects
Drug Resistance, Neoplasm drug effects
Drug Synergism
Ethacrynic Acid therapeutic use
Female
Humans
MAP Kinase Signaling System drug effects
MCF-7 Cells
Mice, Inbred BALB C
Protein Kinase Inhibitors therapeutic use
Quinazolines pharmacology
Quinazolines therapeutic use
Quinolines pharmacology
Quinolines therapeutic use
Wnt Signaling Pathway drug effects
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Antineoplastic Combined Chemotherapy Protocols pharmacology
Breast Neoplasms drug therapy
ErbB Receptors antagonists & inhibitors
Ethacrynic Acid pharmacology
Protein Kinase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 36
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 27487128
- Full Text :
- https://doi.org/10.18632/oncotarget.10846