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

Abstract：

:PEP005 is a novel ingenol angelate that modulates protein kinases C (PKC) functions by activating PKC delta and inhibiting PKC alpha. 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 IC(50) of PEP005 ranged from 0.01-140 microM. 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 microM. Exposure to PEP005 also induced accumulation of cells in the G1 phase of the cell cycle. In addition, PEP005 increased the phosphorylation of PKC delta 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.

journal_name

Br J Cancer

journal_title

British journal of cancer

authors

Benhadji KA,Serova M,Ghoul A,Cvitkovic E,Le Tourneau C,Ogbourne SM,Lokiec F,Calvo F,Hammel P,Faivre S,Raymond E

doi

10.1038/sj.bjc.6604642

subject

Has Abstract

pub_date

2008-12-02 00:00:00

pages

1808-15

issue

11

eissn

0007-0920

issn

1532-1827

pii

6604642

journal_volume

99

pub_type

杂志文章

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