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Blood, 15 August 2005, Vol. 106, No. 4, pp. 1362-1368. Prepublished online as a Blood First Edition Paper on April 21, 2005; DOI 10.1182/blood-2004-10-4117. This Article Full Text (PDF) All Versions of this Article: 2004-10-4117v1 106/4/1362    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hampson, P. Articles by Lord, J. M Search for Related Content PubMed PubMed Citation Articles by Hampson, P. Articles by Lord, J. M Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 27, 2004 Accepted April 9, 2005 PEP005, a selective small molecule activator of protein kinase C, has potent anti-leukemic activity mediated via the delta isoform of PKC Peter Hampson, Hema Chahal, Farhat Khanim, Rachel Hayden, Anneke Mulder, Lakhvir Kaur Assi, Christopher M Bunce, and Janet M Lord* MRC Centre for Immune Regulation and Department of Biosciences, University of Birmingham, Birmingham, United Kingdom * Corresponding author; email: j.m.lord{at}bham.ac.uk. Ingenol 3-angelate (PEP005) is a selective small molecule activator of Protein Kinase C extracted from the plant Euphorbia peplus, whose sap has been used as a traditional medicine for the treatment of skin conditions including warts and cancer. We report here that PEP005 also has potent anti-leukemic effects, inducing apoptosis in myeloid leukemia cell lines and primary acute myeloid leukemia (AML) cells at nanomolar concentrations. Importantly PEP005 did not induce apoptosis in normal CD34+ve cord blood myeloblasts at up to two log concentrations higher than those required to induce cell death in primary AML cells. The effects of PEP005 were PKC dependent and PEP005 efficacy correlated with expression of PKC-delta. The delta isoform of PKC plays a key role in apoptosis and is therefore a rational potential target for anti-leukemic therapies. Transfection of KG1a leukemia cells, that did not express PKC-delta or respond to PEP005, with EGFP-PKC-delta restored sensitivity to induction of apoptosis by PEP005. Our data therefore suggest that activation of PKC-delta provides a novel approach for treatment of acute myeloid leukemia and that screening for PKC-delta expression may identify patients for potential responsiveness to PEP005. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Ghoul, M. Serova, L. Astorgues-Xerri, I. Bieche, G. Bousquet, M. Varna, M. Vidaud, E. Phillips, S. Weill, K. A. Benhadji, et al. Epithelial-to-Mesenchymal Transition and Resistance to Ingenol 3-Angelate, a Novel Protein Kinase C Modulator, in Colon Cancer Cells Cancer Res., May 15, 2009; 69(10): 4260 - 4269. [Abstract] [Full Text] [PDF] A. J. Redig, A. Sassano, B. Majchrzak-Kita, E. Katsoulidis, H. Liu, J. K. Altman, E. N. Fish, A. Wickrema, and L. C. Platanias Activation of Protein Kinase C{eta} by Type I Interferons J. Biol. Chem., April 17, 2009; 284(16): 10301 - 10314. [Abstract] [Full Text] [PDF] M. Serova, A. Ghoul, K. A. Benhadji, S. Faivre, C. Le Tourneau, E. Cvitkovic, F. Lokiec, J. Lord, S. M. Ogbourne, F. Calvo, et al. Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells Mol. Cancer Ther., April 1, 2008; 7(4): 915 - 922. [Abstract] [Full Text] [PDF] S.-J. Cozzi, P. G. Parsons, S. M. Ogbourne, J. Pedley, and G. M. Boyle Induction of Senescence in Diterpene Ester-Treated Melanoma Cells via Protein Kinase C-Dependent Hyperactivation of the Mitogen-Activated Protein Kinase Pathway. Cancer Res., October 15, 2006; 66(20): 10083 - 10091. [Abstract] [Full Text] [PDF]

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