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Research Articles: Therapeutics, Targets, and Development

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

¹ Institut National de la Sante et de la Recherche Medicale-U728-RAYLAB and Department of Medical Oncology, Beaujon University Hospital, Clichy, France; ² Institut National de la Sante et de la Recherche Medicale-U716, Saint-Louis Hospital, Paris, France; ³ AAI Oncology, Kremlin-Bicetre, France; ⁴ Rene-Huguenin Cancer Center, Saint-Cloud, France; ⁵ MRC Center for Immune Regulation, Birmingham, United Kingdom; and ⁶ Peplin Ltd., Newstead, Queensland, Australia

Requests for reprints: Eric Raymond, Department of Medical Oncology, Service Inter-Hospitalier de Cancerologie Bichat-Beaujon, Beaujon University Hospital, 100 Boulevard du General Leclerc, 92110 Clichy, France. Phone: 33-140875617; Fax: 33-140875487. E-mail: eric.raymond{at}bjn.aphp.fr

Abstract

PEP005 (ingenol-3-angelate) is a novel anticancer agent extracted from Euphorbia peplus that was previously shown to modulate protein kinase C (PKC), resulting in antiproliferative and proapoptotic effects in several human cancer cell lines. In Colo205 colon cancer cells, exposure to PEP005 induced a time- and concentration-dependent decrease of cells in S phase of cell cycle and apoptosis. In Colo205 cells exposed to PEP005, a variety of signaling pathways were activated as shown by increased phosphorylation of PKC, Raf1, extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK), c-Jun NH₂-terminal kinase, p38 MAPK, and PTEN. PEP005-induced activation of PKC was associated with its translocation from the cytosol to the nucleus and other cellular membranes. Interestingly, PEP005 treatment also resulted in reduced expression of PKC and reduced levels of phosphorylated active form of AKT/protein kinase B. These data suggest that PEP005-induced activation of PKC and reduced expression of PKC resulted in apoptosis by mechanisms mediated by activation of Ras/Raf/MAPK and inhibition of the phosphatidylinositol 3-kinase/AKT signaling pathways. This study supports ongoing efforts targeting PKC isoforms in cancer therapy with PEP005 alone and in combination with other cytotoxic agents. [Mol Cancer Ther 2008;7(4):915–22]

Grant support: Peplin Ltd. The work in J. Lord's laboratory was also supported by the European Commission (Integrated project LSHB-CT-2004-503467).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: A. Ghoul and M. Serova contributed equally to this work and shall be considered as joint first authors.

⁷ http://www.scioncorp.com

Received 9/10/07; revised 12/13/07; accepted 12/29/07.