title: Malabaricone-A induces a redox imbalance that mediates apoptosis in U937 cell line.
abstract: BACKGROUND
  The 'two-faced' character of reactive oxygen species (ROS) plays an important role in cancer biology by acting both as secondary messengers in intracellular signaling cascades and sustaining the oncogenic phenotype of cancer cells, while on the other hand, it triggers an oxidative assault that causes a redox imbalance translating into an apoptotic cell death.
  
  
  RESULTS
  Using a tetrazolium [{3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl}-2H-tetrazolium] based cell viability assay, we evaluated the cytotoxicity of a plant derived diarylnonanoid, malabaricone-A on leukemic cell lines U937 and MOLT-3. This cytotoxicity hinged on its ability to cause a redox imbalance via its ability to increase ROS, measured by flow cytometry using 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and by decreasing glutathione peroxidase activity. This redox imbalance mediated apoptosis was evident by an increase in cytosolic [Ca(2+)], externalization of phosphatidyl serine as also depolarization of the mitochondrial membrane potential as measured by flow cytometry. There was concomitant peroxidation of cardiolipin, release of free cytochrome c to cytosol along with activation of caspases 9, 8 and 3. This led to cleavage of the DNA repair enzyme, poly (ADP-ribose) polymerase that caused DNA damage as proved by labeling with 4',6-diamidino-2-phenylindole (DAPI); furthermore, terminal deoxy ribonucleotide transferase catalysed incorporation of deoxy uridine triphosphate confirmed DNA nicking and was accompanied by arrest of cell cycle progression.
  
  
  CONCLUSIONS
  Taken together, compounds like MAL-A having pro-oxidant activity mediate their cytotoxicity in leukemic cells via induction of oxidative stress triggering a caspase dependent apoptosis.
authors.affiliation: Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.
authors.forename: Alak
authors.initials: A
authors.lastname: Manna
authors.forename: Piu
authors.initials: P
authors.lastname: Saha
authors.forename: Avijit
authors.initials: A
authors.lastname: Sarkar
authors.forename: Debanjan
authors.initials: D
authors.lastname: Mukhopadhyay
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Bauri
authors.forename: Deepak
authors.initials: D
authors.lastname: Kumar
authors.forename: Padma
authors.initials: P
authors.lastname: Das
authors.forename: Subrata
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: Mitali
authors.initials: M
authors.lastname: Chatterjee
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D053904:DNA Breaks, Single-Stranded / Q000187:drug effects; D005456:Fluorescent Dyes / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012118:Resorcinols / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D005456:Fluorescent Dyes; D016877:Oxidants; D017382:Reactive Oxygen Species; D012118:Resorcinols; C522672:malabaricone A