The synthesis of α,β-unsaturated carbonyl derivatives with the ability to inhibit both glutathione S-transferase P1-1 activity and the proliferation of leukemia cells

Zhao, Guisen; Liu, Chuan; Wang, Rui; Song, Dandan; Wang, Xiaobing; Lou, Hongxiang; Jing, Yongkui

doi:10.1016/j.bmc.2007.01.037

Cited by 23 publications

(34 citation statements)

References 11 publications

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“…Ethacrynic acid at high concentrations induces cell death and apoptosis (10,37) and several groups, including ours, found that the cytotoxic effect of ethacrynic acid requires the a,b-unsaturated carbonyl group (7,9,38). Disruption of the a,b-unsaturated carbonyl group abrogates the cytotoxic effect of ethacrynic acid (7).…”

Section: Discussionmentioning

confidence: 62%

“…Disruption of the a,b-unsaturated carbonyl group abrogates the cytotoxic effect of ethacrynic acid (7). Ethacrynic acid esters containing the a,b-unsaturated carbonyl group induce cell death at much lower concentration than ethacrynic acid (7,12).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

“…One reason was thought to be that the plasma concentration of ethacrynic acid achieved in patients was so low that it may not efficiently inhibit GSTP1-1 activity (6). To improve the ability of ethacrynic acid to inhibit GSTP1-1 activity, we conducted structural modifications and found that esters of ethacrynic acid were more effective than ethacrynic acid in inhibiting GSTP1-1 activity (7,8). To further improve the activity of ethacrynic acid, we synthesized novel ethacrynic acid derivatives containing a heterocyclic oxadiazole and found that ethacrynic acid oxadiazoles were more potent cell growth inhibitors in human leukemia HL-60 cells than ethacrynic acid, even those with a decreased ability of inhibiting GSTP1-1 activity (8).…”

Section: Introductionmentioning

confidence: 99%

“…By conducting structural activity analyses, it was found that the a-, b-unsaturated carbonyl structure is required for its ability to inhibit leukemia cell growth (7,11). We found that ethacrynic acid esters containing the a-, b-unsaturated carbonyl structure have increased abilities of inducing cell death in leukemia cells (7). Focusing on one of these ethacrynic acid esters, ethacrynic acid butyl-ester (EABE), we found that it exhibited greater cell growth inhibition and apoptosis induction abilities than did ethacrynic acid (12).…”

Section: Introductionmentioning

confidence: 99%

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Ethacrynic Acid Oxadiazole Analogs Induce Apoptosis in Malignant Hematologic Cells through Downregulation of Mcl-1 and c-FLIP, Which Was Attenuated by GSTP1-1

Liu

Wang

et al. 2013

Molecular Cancer Therapeutics

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Ethacrynic acid, a diuretic, inhibits glutathione S-transferase P1-1 (GSTP1-1) activity and induces cell death in malignant cells at high concentrations. To improve ethacrynic acid activity, ethacrynic acid oxadiazole analogs 6s and 6u were synthesized. Although both compounds have greater antiproliferative effects than ethacrynic acid in human HL-60 cells, 6u has a reduced ability to inhibit GSTP1-1 activity. The mechanisms of both 6s-and 6u-induced cell death as well as the role of GSTP1-1 in their actions were studied. Both 6s and 6u equally induced apoptosis in HL-60 cells due to the activation of caspase-3, -9, and -8, which was correlated with the downregulation of antiapoptotic proteins c-FLIP, Mcl-1, and XIAP. The caspase inhibitor Z-VAD-FMK blocked the reduction of XIAP, but not of c-FLIP and Mcl-1, in 6s-treated cells. The reduction of c-FLIP and Mcl-1 by 6s was not blocked by the proteasomal inhibitor MG132, but was correlated with inhibition of the phosphorylation of extracellular signal-regulated kinase (ERK) and eIF4E. Both 6s and 6u decreased the intracellular glutathione (GSH) levels. N-acetylcysteine blocked reduction in the levels of Mcl-1, c-FLIP, and intracellular GSH as well as apoptosis in HL-60 cells treated by either compound. Silencing of GSTP1-1 in K562 cells sensitized, but overexpression of GSTP1-1 in Raji cells blocked, apoptosis induction by either compound. GSH conjugation at the methylene group abrogated the ability of inducing apoptosis. These data suggest that the methylene group plays an important role in the downregulation of c-FLIP and Mcl-1 proteins and apoptosis induction, which is inactivated by GSTP1-1 by forming GSH conjugates.

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