Translational Therapeutics

British Journal of Cancer (2008) 99, 1808–1815. doi:10.1038/sj.bjc.6604642 www.bjcancer.com
Published online 25 November 2008

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

K A Benhadji1,2, M Serova1, A Ghoul1,2, E Cvitkovic1, C Le Tourneau1, S M Ogbourne3, F Lokiec2, F Calvo4, P Hammel1, S Faivre1 and E Raymond1

  1. 1INSERM U728, RayLab, Department of Medical Oncology, Beaujon University Hospital, APHP, Paris 7, 100 boulevard Général Leclerc, Clichy 92110, France
  2. 2Department of clinical Pharmacology, René Huguenin Cancer Center, 35 rue Dailly, Saint-Cloud 92210, France
  3. 3Peplin Ltd, 1 Breakfast Creek Road, Newstead Brisbane, Queensland 4006, Australia
  4. 4INSERM U716 IGM-Saint-Louis Hospital, APHP, Paris 7, 27 rue Juliette Dodu, Paris 75010, France

Correspondence: Professor E Raymond, E-mail: eric.raymond@bjn.aphp.fr

Revised 4 August 2008; Accepted 6 August 2008.

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Abstract

PEP005 is a novel ingenol angelate that modulates protein kinases C (PKC) functions by activating PKCdelta and inhibiting PKCalpha. This study assessed 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. PEP005 displayed antiproliferative effects at clinically relevant concentrations with a unique cytotoxicity profile that differs from that of most other investigated cytotoxic agents, including staurosporine. In a subset of colon cancer cells, the IC50 of PEP005 ranged from 0.01–140 muM. The antiproliferative effects of PEP005 were shown to be concentration- and time-dependent. In Colo205 cells, apoptosis induction was observed at concentrations ranging from 0.03 to 3 muM. Exposure to PEP005 also induced accumulation of cells in the G1 phase of the cell cycle. In addition, PEP005 increased the phosphorylation of PKCdelta and p38. In Colo205 cells, combinations of PEP005 with several cytotoxic agents including oxaliplatin, SN38, 5FU, gemcitabine, doxorubicin, vinorelbine, and docetaxel yielded sequence-dependent antiproliferative effects. Cell cycle blockage induced by PEP005 in late G1 lasted for up to 24 h and therefore a 24 h lag-time between PEP005 and subsequent exposure to cytotoxics was required to optimise PEP005 combinations with several anticancer agents. These data support further evaluation of PEP005 as an anticancer agent and may help to optimise clinical trials with PEP005-based combinations in patients with solid tumours.

Keywords:

PKCalpha, PKCdelta, P38, drug resistance, schedule dependency