IMR Press / FBE / Volume 3 / Issue 4 / DOI: 10.2741/E331

Frontiers in Bioscience-Elite (FBE) is published by IMR Press from Volume 13 Issue 2 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Article
NPB001-05 inhibits Bcr-Abl kinase leading to apoptosis of imatinib-resistant cells
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1 Department of Pharmacology, Piramal Life Sciences Limited, 1-Nirlon complex, Goregaon, 400063 Mumbai, India
2 Chemistry Division, Indian Institute of Chemical Biology (IICB, CSIR), 700032 Kolkata, India
3 Division of Infectious Diseases and Immunology, Indian Institute of Chemical Biology (IICB, CSIR), 700032 Kolkata, India

*Author to whom correspondence should be addressed.

Academic Editor: Hala Gali-Muhtasib

Front. Biosci. (Elite Ed) 2011, 3(4), 1273–1288; https://doi.org/10.2741/E331
Published: 1 June 2011
(This article belongs to the Special Issue New emerging anticancer lead compounds from plants)
Abstract

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.

Keywords
Chronic myelogenous leukemia
Piper betle
imatinib
Bcr-Abl
kinase mutation
T315I
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