title: ICB3E induces iNOS expression by ROS-dependent JNK and ERK activation for apoptosis of leukemic cells.
abstract: The role of c-Jun N terminal Kinase (JNK) has been well documented in various cellular stresses where it leads to cell death. Similarly, extracellular signal-regulated kinase (ERK) which was identified as a signalling molecule for survival pathway has been shown recently to be involved in apoptosis also. Recently we reported that ICB3E, a synthetic analogue of Piper betle leaf-derived apoptosis-inducing agent hydroxychavicol (HCH), possesses anti-chronic myeloid leukemia (CML) acitivity in vitro and in vivo without insight on mechanism of action. Here we report that ICB3E is three to four times more potent than HCH in inducing apoptosis of leukemic cells without having appreciable effects on normal human peripheral blood mononuclear cells, mouse fibroblast cell line NIH3T3 and monkey kidney epithelial cell line Vero. ICB3E causes early accumulation of mitochondria-derived reactive oxygen species (ROS) in K562 cells. Unlike HCH, ICB3E treatment caused ROS dependent activation of both JNK, ERK and induced the expression of iNOS leading to generation of nitric oxide (NO). This causes cleavage of caspase 9, 3 and PARP leading to apoptosis. Lack of cleavage of caspase 8 and inability of blocking chimera antibody to DR5 or neutralizing antibody to Fas to reverse ICB3E-mediated apoptosis suggest the involvement of only intrinsic pathway. Our data reveal a novel ROS-dependent JNK/ERK-mediated iNOS activation pathway which leads to NO mediated cell death by ICB3E.
authors.affiliation: Division of Cancer and Cell Biology, Council of Scientific and Industrial Research, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Jadavpur, Kolkata, India.
authors.forename: Nabendu
authors.initials: N
authors.lastname: Biswas
authors.forename: Sanjit K
authors.initials: SK
authors.lastname: Mahato
authors.forename: Avik Acharya
authors.initials: AA
authors.lastname: Chowdhury
authors.forename: Jaydeep
authors.initials: J
authors.lastname: Chaudhuri
authors.forename: Anirban
authors.initials: A
authors.lastname: Manna
authors.forename: Jayaraman
authors.initials: J
authors.lastname: Vinayagam
authors.forename: Sourav
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Parasuraman
authors.initials: P
authors.lastname: Jaisankar
authors.forename: Utpal
authors.initials: U
authors.lastname: Chaudhuri
authors.forename: Santu
authors.initials: S
authors.lastname: Bandyopadhyay
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020014:K562 Cells; D007938:Leukemia / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D041681:NIH 3T3 Cells; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000085:Acetates; D017382:Reactive Oxygen Species; D052247:Nitric Oxide Synthase Type II; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases