Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells
Identifieur interne : 008E73 ( Main/Exploration ); précédent : 008E72; suivant : 008E74Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells
Auteurs : K. A. Benhadji [France] ; M. Serova [France] ; A. Ghoul [France] ; E. Cvitkovic [France] ; C. Le Tourneau [France] ; S. M. Ogbourne [Australie] ; F. Lokiec [France] ; F. Calvo [France] ; P. Hammel [France] ; S. Faivre [France] ; E. Raymond [France]Source :
- British journal of cancer [ 0007-0920 ] ; 2008.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Homme.
English descriptors
- KwdEn :
Abstract
PEP005 is a novel ingenol angelate that modulates protein kinases C (PKC) functions by activating PKCδ and inhibiting PKCa. 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 μM. 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 μM. Exposure to PEP005 also induced accumulation of cells in the G I phase of the cell cycle. In addition, PEP005 increased the phosphorylation of PKCδ 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 Gl lasted for up to 24 h and therefore a 24h 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.
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Le document en format XML
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<country>France</country>
<wicri:noRegion>92110</wicri:noRegion>
<wicri:noRegion>100 boulevard Général Leclerc</wicri:noRegion>
<wicri:noRegion>Clichy 92110</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Faivre, S" sort="Faivre, S" uniqKey="Faivre S" first="S." last="Faivre">S. Faivre</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>INSERM U728, RayLab, Department of Medical Oncology, Beau/on University Hospital, APHP, Paris 7, 100 boulevard Général Leclerc</s1>
<s2>Clichy 92110</s2>
<s3>FRA</s3>
<sZ>1 aut.</sZ>
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<sZ>3 aut.</sZ>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>France</country>
<wicri:noRegion>92110</wicri:noRegion>
<wicri:noRegion>100 boulevard Général Leclerc</wicri:noRegion>
<wicri:noRegion>Clichy 92110</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Raymond, E" sort="Raymond, E" uniqKey="Raymond E" first="E." last="Raymond">E. Raymond</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>INSERM U728, RayLab, Department of Medical Oncology, Beau/on University Hospital, APHP, Paris 7, 100 boulevard Général Leclerc</s1>
<s2>Clichy 92110</s2>
<s3>FRA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>4 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>France</country>
<wicri:noRegion>92110</wicri:noRegion>
<wicri:noRegion>100 boulevard Général Leclerc</wicri:noRegion>
<wicri:noRegion>Clichy 92110</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j" type="main">British journal of cancer</title>
<title level="j" type="abbreviated">Br. J. cancer</title>
<idno type="ISSN">0007-0920</idno>
<imprint><date when="2008">2008</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt><title level="j" type="main">British journal of cancer</title>
<title level="j" type="abbreviated">Br. J. cancer</title>
<idno type="ISSN">0007-0920</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antineoplastic agent</term>
<term>Biological activity</term>
<term>Cancerology</term>
<term>Colon cancer</term>
<term>Drug combination</term>
<term>Human</term>
<term>Mitogen-activated protein kinase</term>
<term>Protein kinase C</term>
<term>Protein kinase Cδ</term>
<term>Treatment resistance</term>
<term>Tumor cell</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Cancer du côlon</term>
<term>Anticancéreux</term>
<term>Activité biologique</term>
<term>Protein kinase C</term>
<term>Association médicamenteuse</term>
<term>Homme</term>
<term>Cellule tumorale</term>
<term>Protein kinase Cδ</term>
<term>Mitogen-activated protein kinase</term>
<term>Résistance traitement</term>
<term>Cancérologie</term>
</keywords>
<keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">PEP005 is a novel ingenol angelate that modulates protein kinases C (PKC) functions by activating PKCδ and inhibiting PKCa. 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<sub>50</sub>
of PEP005 ranged from 0.01 - 140 μM. 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 μM. Exposure to PEP005 also induced accumulation of cells in the G I phase of the cell cycle. In addition, PEP005 increased the phosphorylation of PKCδ 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 Gl lasted for up to 24 h and therefore a 24h 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.</div>
</front>
</TEI>
<affiliations><list><country><li>Australie</li>
<li>France</li>
</country>
<region><li>Île-de-France</li>
</region>
<settlement><li>Paris</li>
</settlement>
</list>
<tree><country name="France"><region name="Île-de-France"><name sortKey="Benhadji, K A" sort="Benhadji, K A" uniqKey="Benhadji K" first="K. A." last="Benhadji">K. A. Benhadji</name>
</region>
<name sortKey="Benhadji, K A" sort="Benhadji, K A" uniqKey="Benhadji K" first="K. A." last="Benhadji">K. A. Benhadji</name>
<name sortKey="Calvo, F" sort="Calvo, F" uniqKey="Calvo F" first="F." last="Calvo">F. Calvo</name>
<name sortKey="Cvitkovic, E" sort="Cvitkovic, E" uniqKey="Cvitkovic E" first="E." last="Cvitkovic">E. Cvitkovic</name>
<name sortKey="Faivre, S" sort="Faivre, S" uniqKey="Faivre S" first="S." last="Faivre">S. Faivre</name>
<name sortKey="Ghoul, A" sort="Ghoul, A" uniqKey="Ghoul A" first="A." last="Ghoul">A. Ghoul</name>
<name sortKey="Ghoul, A" sort="Ghoul, A" uniqKey="Ghoul A" first="A." last="Ghoul">A. Ghoul</name>
<name sortKey="Hammel, P" sort="Hammel, P" uniqKey="Hammel P" first="P." last="Hammel">P. Hammel</name>
<name sortKey="Le Tourneau, C" sort="Le Tourneau, C" uniqKey="Le Tourneau C" first="C." last="Le Tourneau">C. Le Tourneau</name>
<name sortKey="Lokiec, F" sort="Lokiec, F" uniqKey="Lokiec F" first="F." last="Lokiec">F. Lokiec</name>
<name sortKey="Raymond, E" sort="Raymond, E" uniqKey="Raymond E" first="E." last="Raymond">E. Raymond</name>
<name sortKey="Serova, M" sort="Serova, M" uniqKey="Serova M" first="M." last="Serova">M. Serova</name>
</country>
<country name="Australie"><noRegion><name sortKey="Ogbourne, S M" sort="Ogbourne, S M" uniqKey="Ogbourne S" first="S. M." last="Ogbourne">S. M. Ogbourne</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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