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Differentiation

Synergistic effect of AS101 and Bryostatin-1 on myeloid leukemia cell differentiation in vitro and in an animal model

Leukemia volume 21, pages 1504–1513 (2007)Cite this article

Abstract

We evaluated the synergistic activity of AS101 (ammonium trichloro-(dioxoethylene-0-0′)-tellurate) with the protein kinase C (PKC) activators, Bryostatin-1 and phorbol-12-myristate-13-acetate (PMA), on human myelocytic leukemia cell differentiation in vitro, and in a mouse model. Use of AS101 with Bryostatin-1 or with a low concentration of PMA resulted in the differentiation of HL-60 cell line to cells with characteristics of macrophages. A similar synergistic effect was found in vivo. Compared with mice treated with AS101 alone or with Bryostatin-1 alone, the infiltration of leukemic cells into the spleen and the peritoneum of mice treated with both compounds, as well as the number of the HL-60 colonies extracted from those organs, were markedly reduced. The antitumor effects were associated with significantly prolonged survival (100% for 125 days) of the treated mice. Finally, the mechanism of action of this antitumor effect was explored, and was found to involve the Ras/extracellular signal-regulated kinase signaling pathway. Combined treatment with AS101 and Bryostatin-1 synergistically increased p21waf1 expression levels independently of p53. Upregulation of p21waf1 was necessary for HL-60 cell differentiation, which was found to be both c-raf-1 and mitogen-activated protein kinase dependent. This study may have implications for the development of strategies to induce differentiation in myeloid leukemias, myelodysplasias and possibly in other malignancies.

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Acknowledgements

We are grateful to Dr Yona Kalechman for helpful discussion and critical reading of this paper. We would like to thank Mr Uri Karo, for the FACS analysis. The skillful secretarial assistance of J Hertzfelt is cordially acknowledged. This study was a part of Michal Hayun's PhD thesis. This work was partly supported by The Safdié Institute for AIDS and Immunology Research; The Dave and Florence Muskovitz Chair in Cancer Research; Mr Norman Cohen; The Comet Walerstein Cancer Research Program and the Intramural Research of the NIH, National Institute of Aging.

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Authors and Affiliations

  1. The Mina and Everard Goodman Faculty of Life Sciences, Safdié Institute for AIDS and Immunology Research, Bar-Ilan University, Ramat-Gan, Israel

    M Hayun, E Okun, R Hayun, M Albeck & B Sredni

  2. Departments of Nephrology and Pathology, Rabin Medical Center, Petah Tikva, Israel

    U Gafter

  3. Gerontology Research Center, National Institute on Aging, NIH, Baltimore, MA, USA

    D L Longo

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  1. M Hayun
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Correspondence to B Sredni.

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Hayun, M., Okun, E., Hayun, R. et al. Synergistic effect of AS101 and Bryostatin-1 on myeloid leukemia cell differentiation in vitro and in an animal model. Leukemia 21, 1504–1513 (2007). https://doi.org/10.1038/sj.leu.2404746

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