title: Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer.
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.
authors.affiliation: National-Regional Key Technology Engineering Laboratory for Synthetic Biology of Medicine, Cancer Research Center, Shenzhen University, Shenzhen, China.|Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen, China.|The Cancer Research Center, Shenzhen University, Shenzhen, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: National-Regional Key Technology Engineering Laboratory for Synthetic Biology of Medicine, Cancer Research Center, Shenzhen University, Shenzhen, China.|Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen, China.|The Cancer Research Center, Shenzhen University, Shenzhen, China.
authors.forename: XinPing
authors.initials: X
authors.lastname: Huang
authors.affiliation: National-Regional Key Technology Engineering Laboratory for Synthetic Biology of Medicine, Cancer Research Center, Shenzhen University, Shenzhen, China.|Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen, China.|The Cancer Research Center, Shenzhen University, Shenzhen, China.
authors.forename: YunLong
authors.initials: Y
authors.lastname: Hu
authors.affiliation: National-Regional Key Technology Engineering Laboratory for Synthetic Biology of Medicine, Cancer Research Center, Shenzhen University, Shenzhen, China.|Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen, China.|The Cancer Research Center, Shenzhen University, Shenzhen, China.
authors.forename: TingTing
authors.initials: T
authors.lastname: Chen
authors.affiliation: National-Regional Key Technology Engineering Laboratory for Synthetic Biology of Medicine, Cancer Research Center, Shenzhen University, Shenzhen, China.|Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen, China.|The Cancer Research Center, Shenzhen University, Shenzhen, China.
authors.forename: BoYa
authors.initials: B
authors.lastname: Peng
authors.affiliation: National-Regional Key Technology Engineering Laboratory for Synthetic Biology of Medicine, Cancer Research Center, Shenzhen University, Shenzhen, China.|Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen, China.|The Cancer Research Center, Shenzhen University, Shenzhen, China.
authors.forename: NingNing
authors.initials: N
authors.lastname: Gao
authors.affiliation: National-Regional Key Technology Engineering Laboratory for Synthetic Biology of Medicine, Cancer Research Center, Shenzhen University, Shenzhen, China.|Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen, China.|The Cancer Research Center, Shenzhen University, Shenzhen, China.
authors.forename: ZhenChao
authors.initials: Z
authors.lastname: Jin
authors.affiliation: National-Regional Key Technology Engineering Laboratory for Synthetic Biology of Medicine, Cancer Research Center, Shenzhen University, Shenzhen, China.|Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen, China.|The Cancer Research Center, Shenzhen University, Shenzhen, China.
authors.forename: TieLiu
authors.initials: T
authors.lastname: Jia
authors.affiliation: Department of Pathophysiology, Chongqing Medical University, Chongqing, China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Shenzhen Conjugenix Pharma-Tech Co. Ltd, Guangdong, China.
authors.forename: ZhuLin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: National-Regional Key Technology Engineering Laboratory for Synthetic Biology of Medicine, Cancer Research Center, Shenzhen University, Shenzhen, China.|Department of Pharmacy, School of Medicine, Health Science Center, Shenzhen University, Shenzhen, China.|The Cancer Research Center, Shenzhen University, Shenzhen, China.
authors.forename: GuangYi
authors.initials: G
authors.lastname: Jin
mesh_terms: D000077716:Afatinib; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D004976:Ethacrynic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D060449:Wnt Signaling Pathway / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011804:Quinolines; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors; C487932:neratinib; D004976:Ethacrynic Acid
keywords: EGFR; breast cancer; ethacrynic acid; tyrosine kinases