[Frontiers in Bioscience E3, 1349-1364, June 1, 2011]
Antitumor activity of NPB001-05, an orally active inhibitor of Bcr-Abl tyrosine kinase
Vilas Wagh1, Prabha Mishra2, Arvind Thakkar2, Vaibhav Shinde1, Somesh Sharma1, Muralidhara Padigaru2, Kalpana Joshi1
1Department of Pharmacology, Piramal Life Sciences Limited, 1-Nirlon complex, Goregaon, 400063 Mumbai, India,2Biomarker Discovery Group, Piramal Life Sciences Limited, 1-Nirlon complex, Goregaon, 400063 Mumbai, India
TABLE OF CONTENTS
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.