Sulindac and its metabolites: Sulindac sulfide and sulindac sulfone enhance cytotoxic effects of arsenic trioxide on leukemic cell lines

Stępnik, Maciej; Ferlińska, Magdalena; Smok-Pieniążek, Anna; Gradecka-Meesters, Dobrosława; Arkusz, Joanna; Stańczyk, Małgorzata

doi:10.1016/j.tiv.2011.04.011

Cited by 5 publications

(1 citation statement)

References 41 publications

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“…Moreover, sulindac has been shown to counteract malignancy [2][3][4][5][6][7][8][9], an effect attributed at least in part to stimulation of apoptosis [9][10][11][12][13][14][15]. Mechanisms considered to participate in stimulation of tumor cell apoptosis by sulindac include altered regulation of gene expression [9,[16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Sulindac Sulfide Induced Stimulation of Eryptosis

Zbidah¹,

Lupescu²,

Yang³

et al. 2012

Cell Physiol Biochem

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Background: Sulindac sulfide, a non-steroidal anti-inflammatory drug (NSAID), stimulates apoptosis of tumor cells and is thus effective against malignancy. In analogy to apoptosis of nucleated cells, erythrocytes may undergo eryptosis, an apoptosis-like suicidal erythrocyte death, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine-exposure at the cell surface. Stimulators of eryptosis include increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i) and ceramide formation. The present study explored, whether sulindac sulfide stimulates eryptosis. Methods: [Ca²⁺]_i was estimated from Fluo-3 fluorescence, cell volume from forward scatter, phosphatidylserine-exposure from binding of fluorescent annexin-V, hemolysis from hemoglobin release, and ceramide abundance utilizing fluorescent antibodies. Results: A 48 h exposure to sulindac sulfide (≤ 20 µM) was followed by significant increase of [Ca²⁺]_i, enhanced ceramide abundance, decreased forward scatter and increased percentage of annexin-V-binding erythrocytes. Sulindac sulfide triggered slight but significant hemolysis. Removal of extracellular Ca²⁺ significantly blunted, but did not abrogate the effect of sulindac sulfide (20 µM) on annexin-V-binding. Conclusion: Sulindac sulfide stimulates the suicidal death of erythrocytes or eryptosis, an effect paralleled by Ca²⁺-entry, ceramide formation, cell shrinkage and phosphatidylserine-exposure.

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Section: Introductionmentioning

confidence: 99%

Sulindac Sulfide Induced Stimulation of Eryptosis

Zbidah¹,

Lupescu²,

Yang³

et al. 2012

Cell Physiol Biochem

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Assessment of the involvement of oxidative stress and Mitogen-Activated Protein Kinase signaling pathways in the cytotoxic effects of arsenic trioxide and its combination with sulindac or its metabolites: sulindac sulfide and sulindac sulfone on human leukemic cell lines

et al. 2011

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The purpose of the study was to characterize the involvement of reactive oxygen species (ROS) in mediating the cytotoxic effects of arsenic trioxide (ATO) in combination with sulindac or its metabolites: sulfide (SS) and sulfone (SF) on human leukemic cell lines. Jurkat, HL-60, K562, and HPB-ALL cells were exposed to the drugs alone or in combinations. Cell viability was measured using WST-1 or XTT reduction tests and ROS production by dichlorodihydrofluorescein diacetate staining (flow cytometry). Modulation of (a) intracellular glutathione (GSH) level was done by using L: -buthionine sulfoximine (BSO) or diethylmaleate (DEM), (b) NADPH oxidase by using diphenyleneiodonium (DPI), and (c) MAP kinases by using SB202190 (p38), SP600125 (JNK), and U0126 (ERK) inhibitors. ATO cytotoxicity (0.5 or 1 μM) was enhanced by sulindacs, with higher activity showed by the metabolites. Strong cytotoxic effects appeared at SS and SF concentrations starting from 50 μM. The induction of ROS production seemed not to be the major mechanism responsible for the cytotoxicity of the combinations. A strong potentiating effect of BSO on ATO cytotoxicity was demonstrated; DEM (10-300 μM) and DPI (0.0025-0.1 μM; 72 h) did not influence the effects of ATO. Some significant decreases in the viability of the cells exposed to ATO in the presence of MAPK inhibitors comparing with the cells exposed to ATO alone were observed; however, the effects likely resulted from a simple additive cytotoxicity of the drugs. The combinations of ATO with sulindacs offer potential therapeutic usefulness.

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Environmental arsenic exposure: From genetic susceptibility to pathogenesis

Minatel

Sage

Anderson

et al. 2018

Environment International

180

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More than 200 million people in 70 countries are exposed to arsenic through drinking water. Chronic exposure to this metalloid has been associated with the onset of many diseases, including cancer. Epidemiological evidence supports its carcinogenic potential, however, detailed molecular mechanisms remain to be elucidated. Despite the global magnitude of this problem, not all individuals face the same risk. Susceptibility to the toxic effects of arsenic is influenced by alterations in genes involved in arsenic metabolism, as well as biological factors, such as age, gender and nutrition. Moreover, chronic arsenic exposure results in several genotoxic and epigenetic alterations tightly associated with the arsenic biotransformation process, resulting in an increased cancer risk. In this review, we: 1) review the roles of inter-individual DNA-level variations influencing the susceptibility to arsenic-induced carcinogenesis; 2) discuss the contribution of arsenic biotransformation to cancer initiation; 3) provide insights into emerging research areas and the challenges in the field; and 4) compile a resource of publicly available arsenic-related DNA-level variations, transcriptome and methylation data. Understanding the molecular mechanisms of arsenic exposure and its subsequent health effects will support efforts to reduce the worldwide health burden and encourage the development of strategies for managing arsenic-related diseases in the era of personalized medicine.

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Sulindac and its metabolites: Sulindac sulfide and sulindac sulfone enhance cytotoxic effects of arsenic trioxide on leukemic cell lines

Cited by 5 publications

References 41 publications

Sulindac Sulfide Induced Stimulation of Eryptosis

Sulindac Sulfide Induced Stimulation of Eryptosis

Assessment of the involvement of oxidative stress and Mitogen-Activated Protein Kinase signaling pathways in the cytotoxic effects of arsenic trioxide and its combination with sulindac or its metabolites: sulindac sulfide and sulindac sulfone on human leukemic cell lines

Environmental arsenic exposure: From genetic susceptibility to pathogenesis

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Sulindac and its metabolites: Sulindac sulfide and sulindac sulfone enhance cytotoxic effects of arsenic trioxide on leukemic cell lines

Cited by 5 publications

References 41 publications

Sulindac Sulfide  Induced Stimulation of Eryptosis

Sulindac Sulfide  Induced Stimulation of Eryptosis

Assessment of the involvement of oxidative stress and Mitogen-Activated Protein Kinase signaling pathways in the cytotoxic effects of arsenic trioxide and its combination with sulindac or its metabolites: sulindac sulfide and sulindac sulfone on human leukemic cell lines

Environmental arsenic exposure: From genetic susceptibility to pathogenesis

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Sulindac Sulfide Induced Stimulation of Eryptosis

Sulindac Sulfide Induced Stimulation of Eryptosis