Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer

Liu, Bing; Huang, Xincheng; Hu, Yunlong; Chen, Tingting; Peng, Boya; Gao, Ningning; Jin, Zhenchao; Jia, Tieliu; Zhang, Na; Wang, Zhulin; Jin, Guangyi

doi:10.18632/oncotarget.10846

Cited by 22 publications

(23 citation statements)

References 27 publications

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“…Patulin has been recently identified as an antimicrobial agent against Salmonella , 20 and ethacrynic acid has been shown to improve the antitumor effects of epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer. 21 Taking into account the modest potency and reported activities of the compounds, we foresee that the hit molecules could be useful starting compounds for the development of macrodomain inhibitors when medicinal chemistry and structural biology methods are combined, especially as there are already several crystal structures of macrodomains, such as MacroD1 4 and MacroD2, 8 available in the Protein Data Bank.…”

Section: Discussionmentioning

confidence: 99%

Development of an Inhibitor Screening Assay for Mono-ADP-Ribosyl Hydrolyzing Macrodomains Using AlphaScreen Technology

et al. 2018

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Protein mono-ADP-ribosylation is a posttranslational modification involved in the regulation of several cellular signaling pathways. Cellular ADP-ribosylation is regulated by ADP-ribose hydrolases via a hydrolysis of the protein-linked ADPribose. Most of the ADP-ribose hydrolases share a macrodomain fold. Macrodomains have been linked to several diseases, such as cancer, but their cellular roles are mostly unknown. Currently, there are no inhibitors available targeting the mono-ADP-ribose hydrolyzing macrodomains. We have developed a robust AlphaScreen assay for the screening of inhibitors against macrodomains having mono-ADP-ribose hydrolysis activity. We utilized this assay for validatory screening against human MacroD1 and identified five compounds inhibiting the macrodomain. Dose-response measurements and an orthogonal assay further validated four of these compounds as MacroD1 inhibitors. The developed assay is homogenous, easy to execute, and suitable for the screening of large compound libraries. The assay principle can also be adapted for other ADP-ribose hydrolyzing macrodomains, which can utilize a biotin-mono-ADP-ribosylated protein as a substrate.

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Section: Discussionmentioning

confidence: 99%

Development of an Inhibitor Screening Assay for Mono-ADP-Ribosyl Hydrolyzing Macrodomains Using AlphaScreen Technology

et al. 2018

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“…Since more than half of the triple-negative (TNBC) breast cancers are related to epidermal growth factor receptor (EGFR), a therapeutic option is the use of tyrosine kinase inhibitors (TKIs). However, it was proven that ethacrynic acid (EA) (due to its α,β-unsaturated ketone group) has a synergistic effect when combined with TKIs in breast cancer treatment [ 137 ]. The synergistic anti-tumor effect of EA and cytokine-induced killer cells (CIK) on hepatocellular carcinoma (HCC) was also demonstrated [ 138 ].…”

Section: Biomedical Applications Of Dendrimersmentioning

confidence: 99%

Applications and Limitations of Dendrimers in Biomedicine

et al. 2020

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Biomedicine represents one of the main study areas for dendrimers, which have proven to be valuable both in diagnostics and therapy, due to their capacity for improving solubility, absorption, bioavailability and targeted distribution. Molecular cytotoxicity constitutes a limiting characteristic, especially for cationic and higher-generation dendrimers. Antineoplastic research of dendrimers has been widely developed, and several types of poly(amidoamine) and poly(propylene imine) dendrimer complexes with doxorubicin, paclitaxel, imatinib, sunitinib, cisplatin, melphalan and methotrexate have shown an improvement in comparison with the drug molecule alone. The anti-inflammatory therapy focused on dendrimer complexes of ibuprofen, indomethacin, piroxicam, ketoprofen and diflunisal. In the context of the development of antibiotic-resistant bacterial strains, dendrimer complexes of fluoroquinolones, macrolides, beta-lactamines and aminoglycosides have shown promising effects. Regarding antiviral therapy, studies have been performed to develop dendrimer conjugates with tenofovir, maraviroc, zidovudine, oseltamivir and acyclovir, among others. Furthermore, cardiovascular therapy has strongly addressed dendrimers. Employed in imaging diagnostics, dendrimers reduce the dosage required to obtain images, thus improving the efficiency of radioisotopes. Dendrimers are macromolecular structures with multiple advantages that can suffer modifications depending on the chemical nature of the drug that has to be transported. The results obtained so far encourage the pursuit of new studies.

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“…Ethacrynic acid (EA), a diuretic drug, is a known inhibitor of human GST and shows an IC50‐value in the range of 4–0.3 μ m depending on the specific isoform of human GST . It is also known to have anticancer properties . We experimentally tested the effect of EA in combination with SFB in a HepG2 cell line through an MTT assay.…”

Section: Resultsmentioning

confidence: 99%

Identification of a co‐target for enhancing efficacy of sorafenib in HCC through a quantitative modeling approach

et al. 2018

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Sorafenib (SFB), a multi-kinase inhibitor, is the only approved drug for treating hepatocellular carcinoma (HCC). However, SFB shows low efficacy in many cases. HCC related mortality therefore remains to be high worldwide. SFB, a multi-kinase inhibitor is also known to modulate the redox homeostasis in cancer cells. To understand the effect of SFB on the redox status, a quantitative understanding of the system is necessary. Kinetic modeling of the relevant pathways is a useful approach for obtaining a quantitative understanding of the pathway dynamics and to rank the individual factors based on the extent of influence they wield on the pathway. Here, we report a comprehensive model of the glutathione reaction network (GSH ), consisting of four modules and includes SFB-induced redox stress. We compared GSH simulations for HCC of six different etiologies with healthy liver, and correctly identified the expected variations in cancer. Next, we studied alterations induced in the system upon SFB treatment and observed differential H O dynamics in all the conditions. Using metabolic control analysis, we identified glutathione S-transferase (GST) as the enzyme with the highest selective control coefficient, making it an attractive co-target for potentiating the action of SFB across all six etiologies. As a proof-of-concept, we selected ethacrynic acid (EA), a known inhibitor of GST, and verified ex vivo that EA synergistically potentiates the cytotoxic effect of SFB. Being an FDA approved drug, EA is a promising candidate for repurposing as a combination therapy with SFB for HCC treatment.

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Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer

Cited by 22 publications

References 27 publications

Development of an Inhibitor Screening Assay for Mono-ADP-Ribosyl Hydrolyzing Macrodomains Using AlphaScreen Technology

Development of an Inhibitor Screening Assay for Mono-ADP-Ribosyl Hydrolyzing Macrodomains Using AlphaScreen Technology

Applications and Limitations of Dendrimers in Biomedicine

Identification of a co‐target for enhancing efficacy of sorafenib in HCC through a quantitative modeling approach

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