title: Antitumor activity of NPB001-05, an orally active inhibitor of Bcr-Abl tyrosine kinase.
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, BaF3P210(BCR-ABL) and BaF3 P210(BCR-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.
authors.affiliation: Department of Pharmacology, Piramal Life Sciences Limited, 1-Nirlon complex, Goregaon, Mumbai, India.
authors.forename: Vilas
authors.initials: V
authors.lastname: Wagh
authors.forename: Prabha
authors.initials: P
authors.lastname: Mishra
authors.forename: Arvind
authors.initials: A
authors.lastname: Thakkar
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Shinde
authors.forename: Somesh
authors.initials: S
authors.lastname: Sharma
authors.forename: Muralidhara
authors.initials: M
authors.lastname: Padigaru
authors.forename: Kalpana
authors.initials: K
authors.lastname: Joshi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001483:Base Sequence; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D004791:Enzyme Inhibitors; C561621:NPB001-05; D010936:Plant Extracts; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl