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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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Related in: MedlinePlus

PEP005–oxaliplatin combinations in Colo205 colon cancer cells. The following four schedules were investigated using the Chou and Talalay method: (A) Exposure of PEP005 for 24 h along with oxaliplatin; (B) PEP005 exposure for 24 h followed by 24 h exposure to oxaliplatin; (C) 24 h exposure to oxaliplatin followed by 24 h exposure to PEP005; and (D) 24 h exposure to PEP005 followed by a 24 h washout period then followed by exposure to oxaliplatin for 24 h.
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fig4: PEP005–oxaliplatin combinations in Colo205 colon cancer cells. The following four schedules were investigated using the Chou and Talalay method: (A) Exposure of PEP005 for 24 h along with oxaliplatin; (B) PEP005 exposure for 24 h followed by 24 h exposure to oxaliplatin; (C) 24 h exposure to oxaliplatin followed by 24 h exposure to PEP005; and (D) 24 h exposure to PEP005 followed by a 24 h washout period then followed by exposure to oxaliplatin for 24 h.

Mentions: Antagonistic effects between PEP005 and cisplatin were observed for all schedules of administration. Concomitant or sequential exposure to PEP005 and oxaliplatin appeared antagonistic in Colo205 cells. However, synergistic effects between the two drugs were observed when a 24 h washout period was included (schedule 4). Synergism between oxaliplatin and PEP005 was observed when Colo205 cells were exposed to oxaliplatin 24 h and 72 h after PEP005 (Figure 4). Combinations of PEP005 with SN38 were also synergistic using sequential exposure. Combinations of PEP005 with 5FU led to various degrees of additive or synergistic activity regardless of the sequence of drug exposure except for concomitant treatment.


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)

PEP005–oxaliplatin combinations in Colo205 colon cancer cells. The following four schedules were investigated using the Chou and Talalay method: (A) Exposure of PEP005 for 24 h along with oxaliplatin; (B) PEP005 exposure for 24 h followed by 24 h exposure to oxaliplatin; (C) 24 h exposure to oxaliplatin followed by 24 h exposure to PEP005; and (D) 24 h exposure to PEP005 followed by a 24 h washout period then followed by exposure to oxaliplatin for 24 h.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: PEP005–oxaliplatin combinations in Colo205 colon cancer cells. The following four schedules were investigated using the Chou and Talalay method: (A) Exposure of PEP005 for 24 h along with oxaliplatin; (B) PEP005 exposure for 24 h followed by 24 h exposure to oxaliplatin; (C) 24 h exposure to oxaliplatin followed by 24 h exposure to PEP005; and (D) 24 h exposure to PEP005 followed by a 24 h washout period then followed by exposure to oxaliplatin for 24 h.
Mentions: Antagonistic effects between PEP005 and cisplatin were observed for all schedules of administration. Concomitant or sequential exposure to PEP005 and oxaliplatin appeared antagonistic in Colo205 cells. However, synergistic effects between the two drugs were observed when a 24 h washout period was included (schedule 4). Synergism between oxaliplatin and PEP005 was observed when Colo205 cells were exposed to oxaliplatin 24 h and 72 h after PEP005 (Figure 4). Combinations of PEP005 with SN38 were also synergistic using sequential exposure. Combinations of PEP005 with 5FU led to various degrees of additive or synergistic activity regardless of the sequence of drug exposure except for concomitant treatment.

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