Characterization of cell death induced by ethacrynic acid in a human colon cancer cell line DLD‐1 and suppression by <i>N</i>‐acetyl‐<scp>l</scp>‐cysteine

Aizawa, Shu; Ookawa, Keizou; Kudo, Toshihiro; Asano, Junpei; Hayakari, Makoto; Tsuchida, Shigeki

doi:10.1111/j.1349-7006.2003.tb01371.x

Cited by 46 publications

(57 citation statements)

References 42 publications

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“…Several studies have shown that the depletion of GSH by EA results in an oxidant stress that causes cell death (21,22). In addition, it has been suggested that activation of the MAPK pathway may also participate in the cell death process induced by EA (19). The structure of EA has been modified, and we found that EA esters retained GSTP1-1 inhibition ability and also had an increased ability to inhibit leukemia cell growth (23).…”

Section: Introductionmentioning

confidence: 82%

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Ethacrynic Acid Butyl-Ester Induces Apoptosis in Leukemia Cells through a Hydrogen Peroxide–Mediated Pathway Independent of GlutathioneS-Transferase P1-1 Inhibition

Wang

Song

et al. 2007

Cancer Research

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Ethacrynic acid (EA), a glutathione S-transferase inhibitor and diuretic agent, inhibits cell growth and induces apoptosis in cancer cells. To improve the activities, the structure of EA has been modified, and it has been shown that EA esters had an increased cell growth inhibitory ability compared with nonesterified analogue. EA butyl-ester (EABE) was synthesized, and its apoptosis induction ability was studied. The efficacy of EABE was compared with that of EA, and the mechanisms of action were studied in HL-60 leukemia cells. EABE exhibited greater cell growth inhibitory and apoptosis induction abilities than did EA. EABE-induced apoptosis in HL-60 cells correlated with increased levels of reactive oxygen species, the death receptor 5 (DR5), and caspase activation and decreased levels of the mitochondrial membrane potential. Pretreatment with antioxidants, either N-acetylcysteine or catalase, completely blocked EABE-induced apoptosis, H 2 O 2 accumulation, and up-regulation of DR5 levels. RG19, a subclone of Raji cells stably transfected with a GSTP expression vector, and K562 cells with high endogenous GSTP1-1 activity were less sensitive to EABE-induced apoptosis. EABE was more rapidly taken up than EA by HL-60 cells as determined by high-performance liquid chromatography (HPLC) measurements of intracellular concentrations. These results suggest that (a) H 2 O 2 production is a mediator of EABE and EAinduced apoptosis; (b) GSTP1-1 plays a negative role in EABE and EA-induced apoptosis; and (c) the activity of EABE is greater than EA due to its more rapid entry into cells. [Cancer Res 2007;67(16):7856-64]

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Section: Introductionmentioning

confidence: 82%

“…EA inhibits cell growth and induces apoptosis in tumor cells at high concentrations by an unknown mechanism (19,20). Several studies have shown that the depletion of GSH by EA results in an oxidant stress that causes cell death (21,22).…”

Section: Introductionmentioning

confidence: 99%

Ethacrynic Acid Butyl-Ester Induces Apoptosis in Leukemia Cells through a Hydrogen Peroxide–Mediated Pathway Independent of GlutathioneS-Transferase P1-1 Inhibition

Wang

Song

et al. 2007

Cancer Research

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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: 99%

“…Although ethacrynic acid is considered a GSTP1-1 inhibitor, ethacrynic acid alone has been reported to be cytotoxic in many malignant cells (9,10). 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).…”

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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Anti‐cancer Applications of Titanocene‐Functionalised Nanostructured Systems: An Insight into Cell Death Mechanisms

Ceballos-Torres

Virág

Cenariu

et al. 2014

Chemistry A European J

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A series of alkenyl-substituted titanocene compounds have been supported on the mesoporous silica-based material KIT-6. The corresponding functionalised materials were completely characterised by different techniques (solid-state multinuclear NMR spectroscopy, IR spectroscopy, N2 adsorption-desorption isotherms, X-ray fluorescence and diffraction, SEM and TEM) to observe the incorporation of the titanocene derivatives on the external surface of the material KIT-6. Both the titanocene compounds and the materials were tested in vitro against a wide variety of human cancer and normal cell lines. A very high cytotoxicity of the synthesised titanocene derivatives (IC50 values in the range of those described in the literature for the most active cytotoxic titanocene compounds), with selectivity towards cancer cell lines was observed. The cytotoxic activity of the materials is the highest reported to date for titanocene-functionalised materials. In addition, higher Ti uptake (from 4 to 23% of the initial amount of Ti) of the cells treated with materials was observed with respect to those treated with "free" titanocene derivatives (which gave Ti uptake values from 0.4 to 4.6% of the initial amount of Ti). Additional experiments with the titanocene derivatives and the functionalised materials revealed that changes to the morphological and functional dynamics of apoptosis occurred when the active titanocene species were incorporated into mesoporous materials. In addition, the materials could induce programmed cell death in tumour cell populations by impairing the damaged DNA repair mechanisms and by upregulation of intrinsic and extrinsic apoptotic signalling pathways.

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Characterization of cell death induced by ethacrynic acid in a human colon cancer cell line DLD‐1 and suppression by N‐acetyl‐l‐cysteine

Cited by 46 publications

References 42 publications

Ethacrynic Acid Butyl-Ester Induces Apoptosis in Leukemia Cells through a Hydrogen Peroxide–Mediated Pathway Independent of GlutathioneS-Transferase P1-1 Inhibition

Ethacrynic Acid Butyl-Ester Induces Apoptosis in Leukemia Cells through a Hydrogen Peroxide–Mediated Pathway Independent of GlutathioneS-Transferase P1-1 Inhibition

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

Anti‐cancer Applications of Titanocene‐Functionalised Nanostructured Systems: An Insight into Cell Death Mechanisms

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