HA14-1 selectively induces apoptosis in Bcl-2-overexpressing leukemia/lymphoma cells, and enhances cytarabine-induced cell death

Leukemia. 2003 Nov;17(11):2074-80. doi: 10.1038/sj.leu.2403102.


The Bcl-2 oncoprotein is commonly overexpressed in hematological malignancy, where it promotes the survival of neoplastic cells. Recently, a small molecule (HA14-1) was reported to bind the surface pocket of Bcl-2 that mediates antiapoptotic interactions, triggering apoptosis in a Bcl-2-transfected cell line. We investigated the activity of this compound in a panel of malignant hematopoietic cell lines. Consistent with its proposed role as a Bcl-2 inhibitor, HA14-1 was most cytotoxic in lines expressing high levels of Bcl-2. In addition, at lower concentrations (5-12.5 muM), the compound predominantly triggered apoptosis. However, at concentrations two-fold higher than this and above, increasing primary necrosis was observed, suggesting the onset of interactions supplementary to Bcl-2 inhibition. In experiments on primary cells, 25 muM HA14-1 induced extensive apoptosis in acute leukemic blasts, but also suppressed normal hematopoietic colony formation to <50% of baseline. Importantly, low-concentration HA14-1 (5 muM) was nontoxic to normal colony-forming cells, whereas it enhanced the cytotoxicity of the antileukemia drug cytarabine in Bcl-2-positive lymphoblastic leukemia cells. In conclusion, our results indicate that HA14-1 at low concentration selectively triggers apoptosis in malignant hematopoietic cells that overexpress Bcl-2. Agents of this class may have particular utility in combination with cytotoxic chemotherapy drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Benzopyrans / pharmacology*
  • Blast Crisis / pathology
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / pathology
  • Cell Death / drug effects
  • Cell Survival / drug effects
  • Cytarabine / toxicity*
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology*
  • Genes, bcl-2*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Leukemia / pathology
  • Lymphoma / pathology
  • Nitriles / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Tumor Cells, Cultured


  • Benzopyrans
  • Enzyme Inhibitors
  • Nitriles
  • Proto-Oncogene Proteins c-bcl-2
  • ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate
  • Cytarabine