title: The novel arsenical Darinaparsin circumvents BRG1-dependent, HO-1-mediated cytoprotection in leukemic cells.
abstract: Darinaparsin (Dar) is a more potent cytotoxic arsenical than arsenic trioxide (ATO). We hypothesized that the increased cytotoxicity of Dar may be because of a decreased cytoprotective response. We observed that, unlike ATO, Dar does not induce heme oxygenase-1 (HO-1), even though it induces expression of other nuclear factor (erythroid-derived 2)-like 2 (NRF2)-dependent detoxifying enzymes to a greater extent than ATO, in both cancer cell lines and patient-derived leukemic cells. This strengthens the emerging evidence, showing that response to reactive oxygen species (ROS) is stimuli specific. Dar treatment prevents recruitment of the transcriptional coregulator Brahma-related gene 1 (BRG1) to the HMOX1 promoter, which is required for HMOX1 expression. The inability of Dar to induce HO-1 correlates with arrest in G2/M cell cycle phase and BRG1 phosphorylation. Inhibition of HO-1 increases the toxicity of ATO, but has no effect on Dar-induced apoptosis. Accordingly, the lack of HO-1 induction is involved in Dar's enhanced antileukemic properties. Our data highlight cytoprotective responses mediated by HO-1 and BRG1 as a novel target for enhancing the therapeutic range of arsenicals.
authors: 1] Department of Oncology, Lady Davis Institute for Medical Research, Segal Cancer Center, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Quebec, Canada [2] Faculty of Medicine, Department of Experimental Medicine, McGill University, Montréal, Quebec, Canada.
authors: N
authors: N
authors: Garnier
authors: L A
authors: LA
authors: Petruccelli
authors: M F
authors: MF
authors: Molina
authors: M
authors: M
authors: Kourelis
authors: S
authors: S
authors: Kwan
authors: Z
authors: Z
authors: Diaz
authors: H M
authors: HM
authors: Schipper
authors: A
authors: A
authors: Gupta
authors: S V
authors: SV
authors: del Rincon
authors: K K
authors: KK
authors: Mann
authors: W H
authors: WH
authors: Miller
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001752:Blast Crisis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D019610:Cytoprotection / Q000187:drug effects*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D001152:Arsenicals; D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins; D010087:Oxides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C515055:darinaparsin; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D005978:Glutathione; D000077237:Arsenic Trioxide