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

Jason Derrick Lickliter, N J Wood, L Johnson, G McHugh, J Tan, F Wood, J Cox, N W Wickham

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Abstract

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
Original languageEnglish
Pages (from-to)2074 - 2080
Number of pages7
JournalLeukemia
Volume17
Issue number11
Publication statusPublished - 2003

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