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Betulinic acid-induced apoptosis in leukemia cells

Abstract

Betulinic acid (BA), a natural component isolated from Birch trees, effectively induces apoptosis in neuroectodermal and epithelial tumor cells and exerts little toxicity in animal trials. Here, we show that BA-induced marked apoptosis in 65% of primary pediatric acute leukemia cells and all leukemia cell lines tested. When compared for in vitro efficiency with conventionally used cytotoxic drugs, BA was more potent than nine out of 10 standard therapeutics and especially efficient in tumor relapse. No crossresistances were found between BA and any cytotoxic drug. Intracellular apoptosis signaling in leukemia tumor cells paralleled the pathway found in neuroectodermal cells involving caspases, but not death receptors. In isolated mitochondria, BA induced release of both cytochrome c and Smac. Taken together, BA potently induces apoptosis in leukemia cells and should be further evaluated as a future drug to treat leukemia.

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Acknowledgements

The skilled technical work of P Berger is kindly appreciated. We thank Brian Seed (Department of Molecular Biology, Massachussets General Hospital, Boston, MA, USA) for kindly providing RIP-negative JURKAT cells, Shao-Cong Sun (Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA, USA) for kindly providing IKKγ negative JURKAT cells, John Hiscott (Lady Davis Institute for Medical Research, Montreal, Quebec, Canada) for kindly providing IκBαNΔ4 overexpressing JURKAT cells, Manfred Wildner (Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, Munich, Germany) for kindly performing statistical analysis, M Peter (University of Chicago, Chicago, IL, USA) for kindly providing anti caspase-8 antibody and Baxter Oncology, Germany, for kindly providing 4-hydroperoxycyclophosphamide. This work was supported by FöFoLe #288 of LMU Muenchen.

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Correspondence to K M Debatin.

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Ehrhardt, H., Fulda, S., Führer, M. et al. Betulinic acid-induced apoptosis in leukemia cells. Leukemia 18, 1406–1412 (2004). https://doi.org/10.1038/sj.leu.2403406

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Keywords

  • betulinic acid
  • leukemia
  • apoptosis

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