Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia

Cell Death Differ. 2007 Sep;14(9):1667-77. doi: 10.1038/sj.cdd.4402168. Epub 2007 May 18.


Bcr-Abl is the cause of Philadelphia-positive (Ph(+)) leukemias and also constitutes their principal therapeutic target, as exemplified by dramatic effects of imatinib mesylate. However, mono-targeting of Bcr-Abl does not always achieve complete leukemia eradication, and additional strategies those enable complete elimination of leukemic cells are desired to develop. Here we demonstrate that INNO-406, a much more active Bcr-Abl tyrosine kinase inhibitor than imatinib, augments the activities of several proapoptotic Bcl-2 homology (BH)3-only proteins (Bim, Bad, Bmf and Bik) and induces apoptosis in Ph(+) leukemia cells via Bcl-2 family-regulated intrinsic apoptosis pathway. ABT-737, an inhibitor of antiapoptotic Bcl-2 and Bcl-X(L), greatly enhanced the apoptosis by INNO-406, even in INNO-406-less sensitive cells with Bcr-Abl point mutations except T315I mutation. In contrast, co-treatment with INNO-406 and other pharmacologic inducers of those BH3-only proteins, such as 17-allylaminogeldanamycin, an heat shock protein-90 inhibitor, or PS-341, a proteasome inhibitor, did not further increase the BH3-only protein levels or sensitize leukemic cells to INNO-406-induced apoptosis, suggesting a limit to how much expression levels of BH3-only proteins can be increased by anticancer agents. Thus, double-barrelled molecular targeting for Bcr-Abl-driven oncogenic signaling and the cell protection by antiapoptotic Bcl-2 family proteins may be the rational therapeutic approach for eradicating Ph(+) leukemic cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / physiology
  • Benzamides
  • Benzoquinones / pharmacology
  • Biphenyl Compounds / metabolism
  • Biphenyl Compounds / pharmacology*
  • Boronic Acids / metabolism
  • Boronic Acids / pharmacology
  • Bortezomib
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Humans
  • Imatinib Mesylate
  • Lactams, Macrocyclic / pharmacology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Mice
  • Nitrophenols / metabolism
  • Nitrophenols / pharmacology*
  • Piperazines / metabolism
  • Piperazines / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Proto-Oncogene Proteins c-bcr / metabolism
  • Pyrazines / metabolism
  • Pyrazines / pharmacology
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacology*


  • ABT-737
  • Antineoplastic Agents
  • Benzamides
  • Benzoquinones
  • Biphenyl Compounds
  • Boronic Acids
  • Lactams, Macrocyclic
  • Nitrophenols
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrazines
  • Pyrimidines
  • Sulfonamides
  • tanespimycin
  • Bortezomib
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-bcr
  • bafetinib