title: Impact of MAPK and PI3K/AKT signaling pathways on Malabaricone-A induced cytotoxicity in U937, a histiocytic lymphoma cell line.
abstract: Intrinsically cancer cells have higher basal levels of reactive oxygen species (ROS), which when augmented by pro-oxidants such as Malabaricone-A (MAL-A) triggers apoptotic cell death, secondary to 'turning on' of the apoptosis related cell signaling pathways. The effects of MAL-A upon key inflammation related signaling molecules were evaluated by western blotting in U937, a histiocytic lymphoma derived cell line. The impact of inhibitors of the pro-apoptotic MAPK and anti-apoptotic PI3K/AKT signaling pathways upon MAL-A induced cytotoxicity and generation of ROS was evaluated by a cell viability assay and flow cytometry respectively in two hematopoietic cell lines, U937 and MOLT3. MAL-A enhanced phosphorylation of the components of the pro-apoptotic pathway, namely ASK1, p38 and JNK. Alongside, MAL-A decreased the phosphorylation of AKT and mTOR. The cytotoxicity of MAL-A was attenuated by inhibitors of p38 and JNK, whereas its cytotoxic potential was enhanced in the presence of a PI3K/AKT inhibitor. Similarly, MAL-A mediated generation of ROS was decreased by inhibitors of p38MAPK and JNK, whereas the PI3K/AKT inhibitor potentiated its generation of ROS. Taken together, MAL-A mediated its cytotoxicity by enhanced generation of ROS via modulation of the apoptosis related cellular signaling pathways and tilting the balance towards a pro-apoptotic scenario. This was achieved via an up-regulation of MAPK (p38 and JNK) along with down-regulation of the PI3K/AKT/mTOR pathway indicating that manipulation of these pathways by compounds such as MAL-A are promising therapeutic targets, worthy of future pharmacological consideration.
authors.affiliation: Dept. of Pharmacology, Institute of Postgraduate Medical Education and Research, 244B, Acharya JC Bose Road, Kolkata 700 020, India.
authors.forename: Alak
authors.initials: A
authors.lastname: Manna
authors.affiliation: Dept. of Pharmacology, Institute of Postgraduate Medical Education and Research, 244B, Acharya JC Bose Road, Kolkata 700 020, India.
authors.forename: Sritama
authors.initials: S
authors.lastname: De Sarkar
authors.affiliation: Dept. of Pharmacology, Institute of Postgraduate Medical Education and Research, 244B, Acharya JC Bose Road, Kolkata 700 020, India.
authors.forename: Soumita
authors.initials: S
authors.lastname: De
authors.affiliation: Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085, India.
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Bauri
authors.affiliation: Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085, India.
authors.forename: Subrata
authors.initials: S
authors.lastname: Chattopadhyay
authors.affiliation: Dept. of Pharmacology, Institute of Postgraduate Medical Education and Research, 244B, Acharya JC Bose Road, Kolkata 700 020, India. Electronic address: ilatim@vsnl.net.
authors.forename: Mitali
authors.initials: M
authors.lastname: Chatterjee
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012118:Resorcinols / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D048670:MAP Kinase Kinase 4; D051058:Oncogene Protein v-akt; D016877:Oxidants; D019869:Phosphatidylinositol 3-Kinases; D017382:Reactive Oxygen Species; D012118:Resorcinols; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C485678:DBF4 protein, human; C522672:malabaricone A; C546842:MTOR protein, human
keywords: MAPK signaling; Malabaricone-A; PI3K/AKT signaling; Pro-oxidant; Reactive oxygen species