title: NPB001-05 inhibits Bcr-Abl kinase leading to apoptosis of imatinib-resistant cells.
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 microg/ml). Moreover, NPB001-05 was highly inhibitory to wild type P210(Bcr-Abl) and P210(Bcr-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.
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: Shailaja
authors.initials: S
authors.lastname: Chile
authors.forename: Sonal
authors.initials: S
authors.lastname: Monahar
authors.forename: Bikas Chandra
authors.initials: BC
authors.lastname: Pal
authors.forename: Santu
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: Somesh
authors.initials: S
authors.lastname: Sharma
authors.forename: Kalpana
authors.initials: K
authors.lastname: Joshi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D009154:Mutation; D009369:Neoplasms / Q000473:pathology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D001549:Benzamides; C561621:NPB001-05; D010879:Piperazines; D010936:Plant Extracts; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl