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Hydroxychavicol, a Piper Betle leaf Component, Induces Apoptosis of CML Cells Through Mitochondrial Reactive Oxygen Species-Dependent JNK and Endothelial Nitric Oxide Synthase Activation and Overrides Imatinib Resistance

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Title Hydroxychavicol, a Piper Betle leaf Component, Induces Apoptosis of CML Cells Through Mitochondrial Reactive Oxygen Species-Dependent JNK and Endothelial Nitric Oxide Synthase Activation and Overrides Imatinib Resistance
 
Creator B. Chakraborty, Jayashree
Mahato, Sanjit Kumar
Joshi, Kalpana
Shinde, Vaibhav
Rakshit, Srabanti
Biswas, Nabendu
Choudhury (Mukherjee), Indrani
Mandal, Labanya
Ganguly, Dipyaman
Chowdhury, Avik Acharya
Jaisankar , P
Chaudhuri, Utpal
Konar, Aditya
Roy, Siddhartha
Bandyopadhyay, Santu
 
Subject Cancer Biology and Inflammatory Disorder Division
Chemistry
Structural Biology & Bioinformatics
 
Description Alcoholic extract of Piper betle (Piper betle L.) leaves was recently
found to induce apoptosis of CML cells expressing wild type and
mutated Bcr-Abl with imatinib resistance phenotype. Hydroxychavicol
(HCH), a constituent of the alcoholic extract of Piper betle
leaves, was evaluated for anti-CML activity. Here, we report that
HCH and its analogues induce killing of primary cells in CML
patients and leukemic cell lines expressing wild type and mutated
Bcr-Abl, including the T315I mutation, with minimal toxicity to normal
human peripheral blood mononuclear cells. HCH causes early
but transient increase of mitochondria-derived reactive oxygen
species. Reactive oxygen species-dependent persistent activation
of JNK leads to an increase in endothelial nitric oxide synthasemediated
nitric oxide generation. This causes loss of mitochondrial
membrane potential, release of cytochrome c from mitochondria,
cleavage of caspase 9, 3 and poly-adenosine diphosphate-ribose
polymerase leading to apoptosis. One HCH analogue was also
effective in vivo in SCID mice against grafts expressing the T315I
mutation, although to a lesser extent than grafts expressing wild
type Bcr-Abl, without showing significant bodyweight loss. Our
data describe the role of JNK-dependent endothelial nitric oxide
synthase-mediated nitric oxide for anti-CML activity of HCH and
this molecule merits further testing in pre-clinical and clinical settings.
 
Publisher Oxford University Press
 
Date 2012
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1620/1/Cancer_Science%2C_2012.pdf
B. Chakraborty, Jayashree and Mahato, Sanjit Kumar and Joshi, Kalpana and Shinde, Vaibhav and Rakshit, Srabanti and Biswas, Nabendu and Choudhury (Mukherjee), Indrani and Mandal, Labanya and Ganguly, Dipyaman and Chowdhury, Avik Acharya and Jaisankar , P and Chaudhuri, Utpal and Konar, Aditya and Roy, Siddhartha and Bandyopadhyay, Santu (2012) Hydroxychavicol, a Piper Betle leaf Component, Induces Apoptosis of CML Cells Through Mitochondrial Reactive Oxygen Species-Dependent JNK and Endothelial Nitric Oxide Synthase Activation and Overrides Imatinib Resistance. Cancer Science, 103 (1). pp. 88-99.
 
Relation http://dx.doi.org/10.1111/j.1349-7006.2011.02107.x
http://www.eprints.iicb.res.in/1620/