ABT-737 is a useful component of combinatory chemotherapies for chronic myeloid leukaemias with diverse drug-resistance mechanisms

Br J Haematol. 2008 Jan;140(2):181-90. doi: 10.1111/j.1365-2141.2007.06899.x. Epub 2007 Nov 20.


The effect of ABT-737, a BH3-mimicking inhibitor for anti-apoptotic Bcl-2 and Bcl-X(L), but not Mcl-1, against Bcr-Abl-positive (Bcr-Abl(+)) leukaemic cells was examined. ABT-737 potently induced apoptosis in Bcr-Abl(+) chronic myeloid leukaemia (CML) cell lines and primary CML samples in vitro and prolonged the survival of mice xenografted with BV173 cells, a CML cell line. Higher expression of anti-apoptotic Bcl-2 proteins reduced cell killing by ABT-737 in each cell line, but there was no correlation between the sensitivities to ABT-737 and the specific expression patterns of Bcl-2 family proteins among cell lines. Thus, the cell killing effect of ABT-737 must be determined not only by the expression patterns of Bcl-2 family proteins but also by other mechanisms, such as high expression of Bcr-Abl, or a drug-efflux pump, in CML cells. ABT-737 augmented the cell killing effect of imatinib in Bcr-Abl(+) cells with diverse drug-resistance mechanisms unless leukaemic cells harboured imatinib-insensitive Abl kinase domain mutations, such as T315I. The combination of homoharringtonine that reduces Mcl-1 enhanced the killing by ABT-737 strongly in Bcr-Abl(+) cells even with T315I mutation. These results suggest that ABT-737 is a useful component of chemotherapies for CML with diverse drug-resistance mechanisms.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects
  • Biphenyl Compounds / pharmacology*
  • Biphenyl Compounds / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Drug Resistance, Neoplasm*
  • Harringtonines / pharmacology
  • Homoharringtonine
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Transplantation
  • Nitrophenols / pharmacology*
  • Nitrophenols / therapeutic use
  • Piperazines / pharmacology
  • Piperazines / therapeutic use
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use
  • Survival Analysis
  • Transplantation, Heterologous
  • Tumor Cells, Cultured


  • ABT-737
  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Biphenyl Compounds
  • Harringtonines
  • Nitrophenols
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • Homoharringtonine