Induction of apoptosis by remoxipride metabolites in HL60 and CD34+/CD19− human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia

McGuinness, Susan M.; Lundström, Jan O.; Ross, David

doi:10.1016/s0009-2797(99)00105-2

Cited by 13 publications

(9 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results allow rationalization of previous findings that only NCQ-344 had the ability to induce both apoptosis and necrosis (8). Necrosis may reflect the ability of the para-quinone of NCQ-344 to deplete GSH and/or modify critical protein thiol residues.…”

Section: Resultssupporting

confidence: 85%

Characterization of Glutathione Conjugates of the Remoxipride Hydroquinone Metabolite NCQ-344 Formed in Vitro and Detection following Oxidation by Human Neutrophils

Erve

Svensson

Euler-Chelpin

et al. 2004

Chem. Res. Toxicol.

View full text Add to dashboard Cite

Remoxipride is an atypical antipsychotic displaying selective binding to the dopamine D2 receptor. Several cases of aplastic anemia led to the withdrawal of remoxipride from the market in December 1993. The remoxipride metabolite NCQ-344 is a hydroquinone while the structural isomer NCQ-436 is a catechol, both of which have been suggested to be capable of forming a reactive para- and ortho-quinone, respectively. Recently, these two remoxipride metabolites were shown to induce apoptosis in human bone marrow progenitor cells. Furthermore, NCQ-344 also caused necrosis of these cells unlike NCQ-436. Although NCQ-344 has been detected in plasma of humans dosed with remoxipride, to date, no experimental evidence for the formation of the corresponding para-quinone has been obtained. Here, we report the detection of three glutathione (GSH) conjugates of NCQ-344 in vitro that were formed following a chemical reaction and characterized by tandem mass spectrometry and for a cyclized conjugate additionally with derivatization and deuterium exchange. In contrast, NCQ-436 did not form a GSH conjugate. Hypochlorous acid oxidized NCQ-344 to the para-quinone while NCQ-436 was resistant to oxidation. Upon incubation with NCQ-344, stimulated human neutrophils produced from 2- to 5-fold greater amounts of glutathione conjugates than unstimulated neutrophils. Ab initio calculations on these remoxipride metabolites indicated that the reaction leading to the respective quinone was spontaneous for the para-quinone (e.g., from NCQ-344) while ortho-quinone (e.g., from NCQ-436) formation was not. These results demonstrate that NCQ-344 is capable of facile formation of a reactive para-quinone capable of reacting with GSH and may rationalize previous findings regarding the biological effects observed in vitro with these two remoxipride metabolites.

show abstract

Section: Resultssupporting

confidence: 85%

Characterization of Glutathione Conjugates of the Remoxipride Hydroquinone Metabolite NCQ-344 Formed in Vitro and Detection following Oxidation by Human Neutrophils

Erve

Svensson

Euler-Chelpin

et al. 2004

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…To further confirm this finding, HL-60 cells were also treated with the hydroquinone and catechol metabolites (NCQ344 and NCQ436, respectively) of the antipsychotic drug remoxipride. These polyphenolic metabolites of remoxipride were selected for study since they are known to induce apoptosis in MPO-rich HL-60 cells, and remoxipride, like benzene, has been associated with induction of aplastic anemia ( , ). When HL-60 cells were treated with NCQ344, the percentage of cells with loss of MTP increased significantly from 13% (control cells) to 51% (Figure ).…”

Section: Resultsmentioning

confidence: 99%

Intrinsic Pathway of Hydroquinone Induced Apoptosis Occurs via Both Caspase-Dependent and Caspase-Independent Mechanisms

Inayat-Hussain

Ross

2005

Chem. Res. Toxicol.

View full text Add to dashboard Cite

The role of mitochondria and apical caspases in apoptosis induced by the benzene metabolite hydroquinone (HQ) remains to be elucidated. Here, we investigated the involvement of mitochondria and activation of the apical caspases-8 and -9 in HQ induced apoptosis in myeloperoxidase (MPO)-rich HL-60 and MPO-deficient Jurkat T cells. Treatment of HL-60 and Jurkat cells with HQ resulted in apoptosis as assessed by phosphatidyl serine (PS) exposure, loss of mitochondrial transmembrane potential (MTP), release of cytochrome c, and processing of apical caspases-8 and -9 and executioner caspase-3. In HQ-treated HL-60 cells, pretreatment with the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (ZVAD), which did not inhibit PS exposure, also failed to abrogate the loss of MTP and release of cytochrome c. However, complete processing of caspase-9 was inhibited in the presence of ZVAD. In marked contrast, in HQ-treated Jurkat cells, ZVAD significantly abrogated PS exposure, loss of MTP, and caspase-9 processing but not release of cytochrome c. Although ZVAD-sensitive caspase-8 processing occurred in both cell types, pretreatment with either fas-receptor blocking ZB4 or fas-ligand NOK1 neutralizing antibodies did not inhibit HQ-induced apoptosis. In conclusion, our results demonstrate that HQ induced apoptosis in Jurkat cells occurs via a ZVAD-inhibitable, caspase-dependent process, while in HL-60 cells, apoptosis occurs predominantly via caspase-independent mechanisms. Our results emphasize that both caspase-dependent and independent mechanisms should be considered in the intrinsic apoptotic pathway induced by HQ.

show abstract

“…Previous studies have used one or both of these cytotoxicity assays and/or the differential dye uptake assay in combination with other assay methods (Edwards and Tolkovsky, 1994;Hardwick et al;Hughes et al, 1996;Burger et al, 1999;Lizard et al, 1999;McGuinness et al, 1999;Sumitomo et al, 1999;DeMeester et al, 1997). However, none have used this specific combination of assays in evaluating apoptosis in breast cancer cell lines.…”

Section: Discussionmentioning

confidence: 99%

Staurosporine-induced apoptosis and hydrogen peroxide-induced necrosis in two human breast cell lines

2003

View full text Add to dashboard Cite

The use of apoptosis-inducing agents in the treatment of malignant cancer is increasingly being considered as a therapeutic approach. In this study, the induction of apoptosis and necrosis was examined in terms of temporal dose responses, comparing a malignant and nonmalignant breast cell line. Staurosporine (SSP)-induced apoptosis and H 2 O 2 -induced necrosis were evaluated by two cytotoxicity assays, neutral red (NR) and methyl-thiazolyl tertrazolium (MTT), in comparison with a differential dye uptake assay, using Hoechst33342/propidium iodide (Hoechst/PI). Confirmatory morphological assessment was also performed by routine resin histology and transmission electron microscopy. Cell viability was assessed over a 0.5 -48 h time course. In nonmalignant HBL-100 cells, 50 nM SSP induced 100% apoptosis after a 48 h exposure, while the same exposure to SSP caused only 4% apoptosis in metastatic T47D cells. Although complete apoptosis of both cell lines was induced by 50 mM SSP, this effect was delayed in T47D (24 h) compared with HBL-100 (4 h). Results also showed that neither MTT or NR can distinguish between the modes of cell death, nor detect the early onset of apoptosis revealed by Hoechst/PI.

show abstract

Induction of apoptosis by remoxipride metabolites in HL60 and CD34+/CD19− human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia

Cited by 13 publications

References 21 publications

Characterization of Glutathione Conjugates of the Remoxipride Hydroquinone Metabolite NCQ-344 Formed in Vitro and Detection following Oxidation by Human Neutrophils

Characterization of Glutathione Conjugates of the Remoxipride Hydroquinone Metabolite NCQ-344 Formed in Vitro and Detection following Oxidation by Human Neutrophils

Intrinsic Pathway of Hydroquinone Induced Apoptosis Occurs via Both Caspase-Dependent and Caspase-Independent Mechanisms

Staurosporine-induced apoptosis and hydrogen peroxide-induced necrosis in two human breast cell lines

Contact Info

Product

Resources

About