NPB001-05 inhibits Bcr-Abl kinase leading to apoptosis of imatinib-resistant cells

Front Biosci (Elite Ed). 2011 Jun 1;3:1273-88. doi: 10.2741/e331.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Benzamides
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / genetics
  • Humans
  • Imatinib Mesylate
  • Mutation
  • Neoplasms / pathology
  • Phosphorylation
  • Piperazines / pharmacology*
  • Plant Extracts / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / genetics
  • Pyrimidines / pharmacology*

Substances

  • Benzamides
  • NPB001-05
  • Piperazines
  • Plant Extracts
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl