title: Sulindac and its metabolites: sulindac sulfide and sulindac sulfone enhance cytotoxic effects of arsenic trioxide on leukemic cell lines.
abstract: The effects of arsenic trioxide (ATO) in combination with sulindac (SUL), sulindac sulfide (SS) or sulindac sulfone (SF) on human (Jurkat, HL-60, K562 and HPB-ALL) and mouse (EL-4) leukemic cell lines were investigated. The cells showed different sensitivity to sulindacs (2.5-200 μM) with SS being the most cytotoxic (72 h WST-1 reduction test). The cytotoxicity of ATO was enhanced by combination with sulindacs. The combination of ATO (1 μM) with SS or SF at concentrations over 50 μM induced considerable cytotoxicity in all cell lines. Normal human lymphocytes exposed for 48 h to the combinations showed smaller decrease in viability. Measurements of Jurkat, HL-60 and K562 cells exposed to ATO (1 μM) and sulindacs (100 μM or 200 μM for K562 cells) indicated apoptosis as the main cell death mechanism. The mitochondrial membrane potential measurements (JC-1 probe) indicated an active involvement of mitochondria in the process. The results did not indicate involvement of an inhibitory effect of the combinations on NF-κB activity in Jurkat, HL-60 and K562 cells.
authors.affiliation: Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, 8 Sw. Teresy St., 91 348 Łódź, Poland. mstep@imp.lodz.pl
authors.forename: Maciej
authors.initials: M
authors.lastname: Stępnik
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ferlińska
authors.forename: Anna
authors.initials: A
authors.lastname: Smok-Pieniążek
authors.forename: Dobrosława
authors.initials: D
authors.lastname: Gradecka-Meesters
authors.forename: Joanna
authors.initials: J
authors.lastname: Arkusz
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Stańczyk
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D004357:Drug Synergism; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D008214:Lymphocytes / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D011419:Propidium / Q000032:analysis; D013194:Staining and Labeling; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D017304:Annexin A5; D000970:Antineoplastic Agents; D001152:Arsenicals; D016328:NF-kappa B; D010087:Oxides; D013467:Sulindac; D011419:Propidium; C025462:sulindac sulfide; C025463:sulindac sulfone; D000077237:Arsenic Trioxide