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.
Highlights
A wide range of carcinogenesis-associated molecules are investigated as possible therapeutic targets in human malignancies
This hydrophobic diterpene ester is referred to as PEP005; it is strongly cytotoxic at high concentrations (100 μg/mL) [3] and at lower concentrations of 10–100 ng/ mL it is a selective activator of Protein kinase C (PKC) [4]
PEP005 is an activator of novel and classical PKC isoenzymes but its pro-apoptotic effects in leukemic cells rely upon the activation of protein kinase C δ (PKCδ) and its translocation from the cytoplasm to the plasma membrane, nuclear membrane and mitochondrial membrane in CHO-K1 cells and acute myelogenous leukemia (AML) cell lines [4]
Summary
A wide range of carcinogenesis-associated molecules are investigated as possible therapeutic targets in human malignancies. Fractionation of the sap yielded several macrocyclic diterpenes with cytotoxic activity or the ability to influence cellular differentiation, and ingenol-3-angelate emerged as a possible anti-cancer agent. This hydrophobic diterpene ester is referred to as PEP005; it is strongly cytotoxic at high concentrations (100 μg/mL) [3] and at lower concentrations of 10–100 ng/ mL it is a selective activator of Protein kinase C (PKC) [4]
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