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The Protein Kinase C Agonist PEP005 (Ingenol 3-Angelate) in the Treatment of Human Cancer: A Balance between Efficacy and Toxicity

1
Section for Hematology, The University of Bergen, Bergen, Norway
2
Division of Hematology, Department of Medicine, Haukeland University Hospital, Norway
3
School of Immunity and Infection, Birmingham University Medical School, Birmingham, UK
*
Author to whom correspondence should be addressed.
Received: 30 November 2009 / Revised: 7 January 2010 / Accepted: 18 January 2010 / Published: 22 January 2010
(This article belongs to the Collection Toxicity and Therapeutic Interventions in the Immune System)
The diterpene ester ingenol-3-angelate (referred to as PEP005) is derived from the plant Euphorbia peplus. Crude euphorbia extract causes local toxicity and transient inflammation when applied topically and has been used in the treatment of warts, skin keratoses and skin cancer. PEP005 is a broad range activator of the classical (α, β, γ) and novel (δ, ε, η, θ) protein kinase C isoenzymes. Direct pro-apoptotic effects of this drug have been demonstrated in several malignant cells, including melanoma cell lines and primary human acute myelogenous leukemia cells. At micromolar concentrations required to kill melanoma cells this agent causes PKC-independent secondary necrosis. In contrast, the killing of leukemic cells occurs in the nanomolar range, requires activation of protein kinase C δ (PKCδ) and is specifically associated with translocation of PKCδ from the cytoplasm to the nuclear membrane. However, in addition to this pro-apoptotic effect the agent seems to have immunostimulatory effects, including: (i) increased chemokine release by malignant cells; (ii) a general increase in proliferation and cytokine release by activated T cells, including T cells derived from patients with chemotherapy-induced lymphopenia; (iii) local infiltration of neutrophils after topical application with increased antibody-dependent cytotoxicity; and (iv) development of specific anti-cancer immune responses by CD8+ T cells in animal models. Published studies mainly describe effects from in vitro investigations or after topical application of the agent, and careful evaluation of the toxicity after systemic administration is required before the possible use of this agent in the treatment of malignancies other than skin cancers. View Full-Text
Keywords: cancer-protein kinase C-PEP005 cancer-protein kinase C-PEP005
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MDPI and ACS Style

Ersvaer, E.; Kittang, A.O.; Hampson, P.; Sand, K.; Gjertsen, B.T.; Lord, J.M.; Bruserud, Ø. The Protein Kinase C Agonist PEP005 (Ingenol 3-Angelate) in the Treatment of Human Cancer: A Balance between Efficacy and Toxicity. Toxins 2010, 2, 174-194. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins2010174

AMA Style

Ersvaer E, Kittang AO, Hampson P, Sand K, Gjertsen BT, Lord JM, Bruserud Ø. The Protein Kinase C Agonist PEP005 (Ingenol 3-Angelate) in the Treatment of Human Cancer: A Balance between Efficacy and Toxicity. Toxins. 2010; 2(1):174-194. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins2010174

Chicago/Turabian Style

Ersvaer, Elisabeth, Astrid Olsnes Kittang, Peter Hampson, Kristoffer Sand, Bjørn Tore Gjertsen, Janet M. Lord, and Øystein Bruserud. 2010. "The Protein Kinase C Agonist PEP005 (Ingenol 3-Angelate) in the Treatment of Human Cancer: A Balance between Efficacy and Toxicity" Toxins 2, no. 1: 174-194. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins2010174

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