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NPB001-05 Inhibits Bcr-Abl Kinase Leading to Apoptosis of Imatinib-Resistant Cells

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Title NPB001-05 Inhibits Bcr-Abl Kinase Leading to Apoptosis of Imatinib-Resistant Cells
 
Creator Wagh, Vilas
Chile, Shailaja
Monahar, Sonal
Pal, Bikas C
Bandyopadhyay, Santu
Sharma, Somesh
Joshi, Kalpana
 
Subject Chemistry
Infectious Diseases and Immunology
 
Description The deregulated activity of the Bcr-Abl tyrosine
kinase provides a rational basis for the development
therapeutics in all phases of Chronic Myelogenous
Leukemia (CML). Although a well studied imatinib
therapy has clinical success against CML, resistance to
imatinib due to mutations in the kinase domain, especially
T315I poses a major problem for the ultimate success of
CML therapy by this agent. Herein we describe an
NPB001-05, derived from extract of Piper betle leafs,
which is highly active in specifically inhibiting Bcr-Abl
expressing cells. NPB001-05 inhibited the proliferation of
BaF3 cells ectopically expressing wild type Bcr-Abl
phenotype and 12 different imatinib-resistant mutations of
clinical relevance (average IC50 5.7 μg/ml). Moreover,
NPB001-05 was highly inhibitory to wild type P210Bcr-Abl
and P210Bcr-Abl-T315I kinase activity and abrogated the
autophosphorylating enzyme in time- and dose- dependent
manner. NPB001-05 was non-toxic on normal cells, but
was inhibitory to CML patient derived peripheral blood
mononuclear cells. Treatment with NPB001-05 caused
apoptosis induction and G0G1 cell cycle arrest in both Bcr-
Abl wild type and T315I mutant cell lines
 
Date 2011
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1621/1/Frontiers_in_Bioscience%2C_2011.pdf
Wagh, Vilas and Chile, Shailaja and Monahar, Sonal and Pal, Bikas C and Bandyopadhyay, Santu and Sharma, Somesh and Joshi, Kalpana (2011) NPB001-05 Inhibits Bcr-Abl Kinase Leading to Apoptosis of Imatinib-Resistant Cells. Frontiers in Bioscience. pp. 1273-1288.
 
Relation http://dx.doi.org/
http://www.eprints.iicb.res.in/1621/