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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.

Benhadji KA, Serova M, Ghoul A, Cvitkovic E, Le Tourneau C, Ogbourne SM, Lokiec F, Calvo F, Hammel P, Faivre S, Raymond E - Br. J. Cancer (2008)

Bottom Line: The antiproliferative effects of PEP005 were shown to be concentration- and time-dependent.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.

View Article: PubMed Central - PubMed

Affiliation: INSERM U728, RayLab, Department of Medical Oncology, Beaujon University Hospital, APHP, Paris 7, 100 boulevard Général Leclerc, Clichy 92110, France.

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.

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Cell cycle effects of anticancer agents alone and in combination with PEP005. Cells were incubated with the indicated drug sequence at IC50 concentrations, washed, and analysed by flow cytometry at 24 h post-incubation in drug-free medium.
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fig5: Cell cycle effects of anticancer agents alone and in combination with PEP005. Cells were incubated with the indicated drug sequence at IC50 concentrations, washed, and analysed by flow cytometry at 24 h post-incubation in drug-free medium.

Mentions: Colo205 cells treated with PEP005-based synergistic combinations were analysed using flow cytometry. Cell cycle distribution, displayed in Figure 5, showed sub-G1 accumulation suggesting apoptosis as a result of PEP005 combinations with doxorubicin, gemcitabine, docetaxel, and vinorelbine. Exposure to oxaliplatin 24 h after the end of exposure to PEP005 led to accumulation of cells in S-phase of cell cycle.


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

Benhadji KA, Serova M, Ghoul A, Cvitkovic E, Le Tourneau C, Ogbourne SM, Lokiec F, Calvo F, Hammel P, Faivre S, Raymond E - Br. J. Cancer (2008)

Cell cycle effects of anticancer agents alone and in combination with PEP005. Cells were incubated with the indicated drug sequence at IC50 concentrations, washed, and analysed by flow cytometry at 24 h post-incubation in drug-free medium.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2600681&req=5

fig5: Cell cycle effects of anticancer agents alone and in combination with PEP005. Cells were incubated with the indicated drug sequence at IC50 concentrations, washed, and analysed by flow cytometry at 24 h post-incubation in drug-free medium.
Mentions: Colo205 cells treated with PEP005-based synergistic combinations were analysed using flow cytometry. Cell cycle distribution, displayed in Figure 5, showed sub-G1 accumulation suggesting apoptosis as a result of PEP005 combinations with doxorubicin, gemcitabine, docetaxel, and vinorelbine. Exposure to oxaliplatin 24 h after the end of exposure to PEP005 led to accumulation of cells in S-phase of cell cycle.

Bottom Line: The antiproliferative effects of PEP005 were shown to be concentration- and time-dependent.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.

View Article: PubMed Central - PubMed

Affiliation: INSERM U728, RayLab, Department of Medical Oncology, Beaujon University Hospital, APHP, Paris 7, 100 boulevard Général Leclerc, Clichy 92110, France.

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.

Show MeSH
Related in: MedlinePlus