The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias

Cell Death Differ. 2008 Nov;15(11):1712-22. doi: 10.1038/cdd.2008.107. Epub 2008 Jul 11.


Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl(+)) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspase-independent pathways. The latter pathways include caspase-independent apoptosis (CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl(+) leukemias.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosomes / drug effects
  • Apoptosomes / metabolism
  • Autophagy / drug effects*
  • Caspases / metabolism
  • Cell Line, Tumor
  • Chloroquine / pharmacology
  • Cytoprotection / drug effects
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Male
  • Mice
  • Mice, SCID
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / pharmacology*
  • Xenograft Model Antitumor Assays


  • Apoptosomes
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Chloroquine
  • Fusion Proteins, bcr-abl
  • Caspases
  • bafetinib