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

Abstract

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.

Reactivation of latent HIV-1 by new semi-synthetic ingenol esters

“…There are several publications describing anti-cancer activities of ingenol esters and the HIV transcription activation properties of this class of drugs (Ersvaer et al, 2010; Fujiwara et al, 1998; Hong et al, 2011; Lee et al, 2010; Warrilow et al, 2006). Ingenol-3-angelate (referred to as PEP005) is derived from the plant Euphorbia peplus and is currently in clinical trials for eradicating basal cell carcinoma, actinic keratosis (a disease associated with photo-damaged skin that may lead to invasive squamous cell carcinoma) and squamous cell carcinoma (SCC) in situ by topical application (Ersvaer et al, 2010; Li et al, 2010.; Song et al, 2013).…”

“…Ingenol derivates can inhibit HIV reverse transcription and down modulate CD4 and CXCR4 surface expression by activating PKC (Ersvaer et al, 2010; Fujiwara et al, 1998; Hong et al, 2011; Lee et al, 2010; Warrilow et al, 2006). Additionally, ingenol 3-angelate has anti-tumor activity and activates responses mediated by PKC pathway, thus being considered a PKC agonist (Ersvaer et al, 2010; Lee et al, 2010). Another semi-synthetic derivative, ingenol 3,20-dibenzoate, displays trombopoietic activity and also activates PKC pathways (Racke et al, 2012).…”

Ingenol Mebutate for Lentigo Maligna: A Case Report

“…Apart from its cytotoxic properties, ingenol mebutate is a protein kinase C activator [15] and induces apoptosis in caspase-dependent way [16] . In an in vitro study on different melanoma cell lines, ingenol mebutate induced cell death in all of the cultured melanoma cell lines.…”

Kinase Regulation by Sulfur and Selenium Containing Compounds

“…Other kinases such as protein kinase C (PKCs) [29], which belong to a family of serine/threonine kinases made up of at least 11 isoenzymes ( , I, II, , , , , μ, , , and / ), have a role in cell proliferation, differentiation, angiogenesis and apoptosis. The PKCs [30] can be activated by a wide range of signals and have different effects on apoptosis (proapoptotic isoenzyme ), though most isoenzymes have antiapoptotic effects (isoenzymes , I, II, , ). PKC and have been linked to increased invasion, proliferation, drug resistance and genetic instability and like PKC , they are thought to be oncogenes.…”