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Enantioselective apoptosis induction in histiocytic lymphoma cells and acute promyelocytic leukemia cells

  • Molecular Toxicology
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Abstract

The aim of this study was to identify valproic acid (VPA) analogs with a broad spectrum of anti-cancer activities and an increased apoptosis-inducing potential compared with the parent VPA, which is enrolled as histone deacetylase (HDAC) inhibitor in a large number of clinical trials. We identified a chiral VPA derivative, (S)-2-pentyl-4-pentynoic acid, previously characterized as HDAC inhibitor that induced massive programmed cell death in a strongly enantioselective manner in U937 histiocytic lymphoma cells and NB4 acute promyelocytic leukemia cells. By performing fluorescence-activated cell sorting and Western blotting analyses, we established that enantiomer (S)-2-pentyl-4-pentynoic acid has higher apoptosis-inducing potential than VPA itself. The optic antipode (R)-2-pentyl-4-pentynoic acid and VPA caused under the same conditions only a weak growth inhibition without inducing cell differentiation and apoptosis. (S)-2-pentyl-4-pentynoic acid is more apoptogenic than VPA and displays enantioselective anti-cancer properties that warrant further research regarding the mechanistic basis of its activity and its potential use in cancer therapy.

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Acknowledgments

This work was supported by European grant NUTRICEPTORS HPRN-CT-2002-00268. Work in the laboratory of HG was supported by the European community (contracts HEALTH-F4-2007-200767 `APO-SYS', LSHC-CT-2005-518417 `EPITRON' and HEALTH-F4-2009-221952 `ATLAS'), the Institut National du Cancer (INCa), the Fondation ARC and the Ligue National contre le Cancer (laboratoire labellisé). The authors thank Dr. Claudine Gaudon, Audrey Bindler-Furst and Michele Lieb for excellent technical assistance.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Institute of Genetics and Molecular Biology of the Cell (IGBMC), 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, Strasbourg, France

    Diana Ivanova & Hinrich Gronemeyer

  2. Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Bischofsholer Damm 15, 30173, Hannover, Germany

    Pablo Steinberg & Heinz Nau

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  1. Diana Ivanova
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  2. Hinrich Gronemeyer
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  3. Pablo Steinberg
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  4. Heinz Nau
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Correspondence to Hinrich Gronemeyer or Pablo Steinberg.

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Ivanova, D., Gronemeyer, H., Steinberg, P. et al. Enantioselective apoptosis induction in histiocytic lymphoma cells and acute promyelocytic leukemia cells. Arch Toxicol 87, 303–310 (2013). https://doi.org/10.1007/s00204-012-0930-3

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  • DOI: https://doi.org/10.1007/s00204-012-0930-3

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