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

• DOI: 10.1038/sj.leu.2403102
• Publication Date: 2003-08-20T20:26:54Z
• Authors: J D Lickliter; N J Wood; L Johnson; G McHugh; J Tan; F Wood; J Cox; N W Wickham
• Keywords: 0301 basic medicine; Leukemia; Cell Death; Lymphoma; Cell Survival; Cytarabine; 610; Apoptosis; Bone Marrow Cells; Drug Synergism; Hematopoietic Stem Cells; Genes, bcl-2; 3. Good health; 03 medical and health sciences; Proto-Oncogene Proteins c-bcl-2; Nitriles; Tumor Cells, Cultured; Humans; Benzopyrans; Enzyme Inhibitors; Blast Crisis

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.