title: Cytoprotective effect of isoniazid against H2O2 derived injury in HL-60 cells.
abstract: To combat tuberculosis (TB), host phagocytic cells need to survive against self-generating oxidative stress-induced necrosis. However, the effect of isoniazid (INH) in protecting cells from oxidative stress-induced necrosis has not been previously investigated. In this in vitro study, the cytotoxic effect of H2O2 generation using glucose oxidase (a model of oxidative stress) was found to be abrogated by INH in a concentration-dependent manner in HL-60 cells (a human promyelocytic leukemia cell). In cells treated with glucose oxidase, both ATP and mitochondrial membrane potential were found to be decreased. However, treatment with INH demonstrated small but significant attenuation in decreasing ATP levels, and complete reversal for the decrease in mitochondrial membrane potential. Quantitative proteomics analysis identified up-regulation of 15 proteins and down-regulation of 14 proteins which all together suggest that these proteomic changes signal for increasing cellular replication, structural integrity, ATP synthesis, and inhibiting cell death. In addition, studies demonstrated that myeloperoxidase (MPO) was involved in catalyzing INH-protein adduct formation. Unexpectedly, these covalent protein adducts were correlated with INH-induced cytoprotection in HL-60 cells. Further studies are needed to determine whether the INH-protein adducts were causative in the mechanism of cytoprotection.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: Saifur R
authors.initials: SR
authors.lastname: Khan
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada; Pharmacology and Toxicology Department, Faculty of Pharmacy, Taibah University, Madinah, Saudi Arabia.
authors.forename: Naif
authors.initials: N
authors.lastname: Aljuhani
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: Andrew G M
authors.initials: AG
authors.lastname: Morgan
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: Argishti
authors.initials: A
authors.lastname: Baghdasarian
authors.affiliation: Department of Biochemistry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada; Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Fahlman
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada. Electronic address: siraki@ualberta.ca.
authors.forename: Arno G
authors.initials: AG
authors.lastname: Siraki
mesh_terms: D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007538:Isoniazid / Q000494:pharmacology*; D009336:Necrosis / Q000139:chemically induced / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D006861:Hydrogen Peroxide; D007538:Isoniazid
keywords: Covalent binding; Cytoprotection; HL-60 cells; Hydrogen peroxide; Isoniazid; Myeloperoxidase