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  • Molecular Targets For Therapy (MTT)
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Molecular Targets for Therapy (MTT)

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

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 μ M), 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 μ M 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 μ M) 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.

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Acknowledgements

We thank Professors Andrew Boyd and Michael Good for critical reading of the manuscript. This work is supported by grants from the Leukaemia Foundation of Queensland and the Townsville Hospital.

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Lickliter, J., Wood, N., Johnson, L. et al. HA14-1 selectively induces apoptosis in Bcl-2-overexpressing leukemia/lymphoma cells, and enhances cytarabine-induced cell death. Leukemia 17, 2074–2080 (2003). https://doi.org/10.1038/sj.leu.2403102

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