PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC.

@article{Hampson2005PEP005AS,
  title={PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC.},
  author={Peter Wright Hampson and Hema Chahal and Farhat L. Khanim and Rachel E. Hayden and Anneke Mulder and Lakhvir Kaur Assi and Christopher M. Bunce and Janet M. Lord},
  journal={Blood},
  year={2005},
  volume={106 4},
  pages={
          1362-8
        }
}
Ingenol 3-angelate (PEP005) is a selective small molecule activator of protein kinase C (PKC) 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 antileukemic effects, inducing apoptosis in myeloid leukemia cell lines and primary acute myeloid leukemia (AML) cells at nanomolar concentrations. Of importance, PEP005 did not induce apoptosis in normal… 

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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

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

Novel Antileukemic Compound Ingenol 3-Angelate Inhibits T Cell Apoptosis by Activating Protein Kinase Cθ*

It is shown that, in contrast to its effect on leukemic cells, PEP005 provides a strong survival signal to resting and activated human T cells, and the expression of functional PKCθ influences whether PKC activation leads to an anti- or proapoptotic outcome in the cell types tested.

Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells

The antiproliferative effects of PEP005 alone and in combination with several other anticancer agents in a panel of 10 human cancer cell lines characterised for expression of several PKC isoforms support further evaluation of P EP005 as an anticancer agent and may help to optimise clinical trials with PEP003-based combinations in patients with solid tumours.

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

Exposure to PEP005 induced a time- and concentration-dependent decrease of cells in S phase of cell cycle and apoptosis in Colo205 colon cancer cells, supporting ongoing efforts targeting PKC isoforms in cancer therapy with PEP003 alone and in combination with other cytotoxic agents.

Yessotoxin activates cell death pathways independent of Protein Kinase C in K-562 human leukemic cell line.

Protein kinase C α and δ are members of a large kinase family of high potential for novel anticancer targeted therapy

Current knowledge on regulation of PKC-δ andPKC-α in cancer progression is focused on highlighting the potential role of those kinases as targets for anticancer therapeutics.

Preclinical and clinical development of novel agents that target the protein kinase C family.

An overview on the current understanding of PKC participation in chemotherapeutic resistance, the possible implications in cancer treatment, and the potential of most recent PKC inhibitors in molecular cancer therapeutics is provided.

Targeting Cutaneous T-Cell Lymphoma Cells by Ingenol Mebutate (PEP005) Correlates with PKCδ Activation, ROS Induction as Well as Downregulation of XIAP and c-FLIP

PEP005 resulted in the activation of proapoptotic PKCδ, and the PKC inhibitor bisindolylmaleimide I reduced apoptosis, caspase-3 processing and ROS production, as well as restored cell viability, suggesting its therapeutic targeting.

Induction of senescence in diterpene ester-treated melanoma cells via protein kinase C-dependent hyperactivation of the mitogen-activated protein kinase pathway.

The in vitro cytostatic effects of PEP005 and the diterpene ester phorbol 12-myristate 13-acetate are described and it is proposed that activation of PKC overstimulates the RAS/RAF/MEK/ERK pathway, resulting in molecular changes leading to the senescent phenotype.

Natural Product Vibsanin A Induces Differentiation of Myeloid Leukemia Cells through PKC Activation.

The results offer a preclinical proof of concept for vibsanin A as a myeloid differentiation-inducing compound, with potential application as an antileukemic agent.
...

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