IMR Press / FBE / Volume 3 / Issue 4 / DOI: 10.2741/E338

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
Antitumor activity of NPB001-05, an orally active inhibitor of Bcr-Abl tyrosine kinase
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1 Department of Pharmacology, Piramal Life Sciences Limited, 1-Nirlon complex, Goregaon, 400063 Mumbai, India
2 Biomarker Discovery Group, Piramal Life Sciences Limited, 1-Nirlon complex, Goregaon, 400063 Mumbai, India

*Author to whom correspondence should be addressed.

Academic Editor: Hala Gali-Muhtasib

Front. Biosci. (Elite Ed) 2011, 3(4), 1349–1364; https://doi.org/10.2741/E338
Published: 1 June 2011
(This article belongs to the Special Issue New emerging anticancer lead compounds from plants)
Abstract

Scientists are constantly searching for phytochemical compounds with anti-cancer activity. In this study, activity of plant extract NPB001-05 from Piper betle was tested on human chronic myelogenous leukemia (CML) xenograft models. NPB001-05 was active when dosed orally (500 mg/kg) once or twice a day in xenograft tumor models. NPB001-05 showed activity to T315I tumor xenograft, where imatinib failed to show antitumor activity. NPB001-05 showed no relevant toxicity in animal models during 2 weeks exposure to drug. Responsive tumor showed inhibition of tyrosine kinase activity with lowered Bcr-Abl protein levels and increased apoptosis. Microarray based transcription profiling studies demonstrated that both imatinib and NPB001-05 dysregulated imatinib- responsive genes. NPB001-05 showed additional genes selectively dysregulated from ER stress, PI3K/AKT, MAPK pathways. Additionally, we tested gene expression of PI3K, AKT1, JUN, CASP3 and DDIT3 in K562, BaF3P210BCR-ABL and BaF3 P210BCR-ABLT315I cell line treated for 6- and 12- hours with NPB001-05 and imatinib. The data indicates that NPB001-05 mediated cell death in K562 affects the function of ER stress. NPB001-05 shows antitumor activity with favorable toxicity profile.

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