AI Article Synopsis
- Ethacrynic acid was linked with ethylenediamine and 1,4-butanediamine, producing EDEA and BDEA, which are effective pro-inhibitors of the enzyme glutathione transferase (GST).
- These compounds demonstrated strong inhibition at extremely low concentrations and effectively targeted GSTmu, enhancing the potential for cancer treatment.
- In laboratory tests on cisplatin-resistant cancer cells, BDEA and EDEA substantially increased cell sensitivity to cisplatin, leading to higher rates of apoptosis and showing promising results in xenograft models.
Article Abstract
The linking of ethacrynic acid with ethylenediamine and 1,4-butanediamine gave EDEA and BDEA, respectively, as membrane-permeable divalent pro-inhibitors of glutathione -transferase (GST). Their divalent glutathione conjugates showed subnanomolar inhibition and divalence-binding to GSTmu (GSTM) (PDB: 5HWL) at ∼0.35 min. In cisplatin-resistant SK-OV-3, COC1, SGC7901 and A549 cells, GSTM activities probed by 15 nM BDEA or EDEA revealed 5-fold and 1.0-fold increases in cisplatin-resistant SK-OV-3 and COC1 cells, respectively, in comparison with the susceptible parental cells. Being tolerable by HEK293 and LO2 cells, BDEA at 0.2 μM sensitised resistant SK-OV-3 and COC1 cells by ∼3- and ∼5-folds, respectively, released cytochrome c and increased apoptosis; EDEA at 1.0 μM sensitised resistant SK-OV-3 and A549 cells by ∼5- and ∼7-fold, respectively. EDEA at 1.7 μg/g sensitised resistant SK-OV-3 cells to cisplatin at 3.3 μg/g in nude mouse xenograft model. BDEA and EDEA are promising leads for probing cellular GSTM and sensitising cisplatin-resistant ovarian cancers.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865112 | PMC |
| http://dx.doi.org/10.1080/14756366.2022.2038591 | DOI Listing |
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Article Synopsis
- Ethacrynic acid was linked with ethylenediamine and 1,4-butanediamine, producing EDEA and BDEA, which are effective pro-inhibitors of the enzyme glutathione transferase (GST).
- These compounds demonstrated strong inhibition at extremely low concentrations and effectively targeted GSTmu, enhancing the potential for cancer treatment.
- In laboratory tests on cisplatin-resistant cancer cells, BDEA and EDEA substantially increased cell sensitivity to cisplatin, leading to higher rates of apoptosis and showing promising results in xenograft models.
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