Ingenol 3-angelate (
PEP005), one of the active ingredients in an extract from Euphorbia peplus, was shown in preclinical studies to have activity against human
melanoma xenografts in nude mice. In the present study, we have tested its ability to induce the apoptosis of
melanoma cells in vitro in the absence or presence of
tumor necrosis factor-related apoptosis inducing
ligand (TRAIL). The results showed that at relatively high concentrations (100 microg/mL),
PEP005 killed
melanoma cells mainly by induction of
necrosis. In 20% of cell lines, evidence of apoptosis was observed. Apoptosis was
caspase-dependent and associated with changes in mitochondrial membrane potential that were not inhibitable by overexpression of Bcl-2 or inhibition of
caspases but were blocked by inhibition of
protein kinase C (PKC). Low concentrations (1 or 10 microg/mL) of
PEP005 either increased or decreased TRAIL-induced apoptosis in a cell line-dependent manner. These changes in TRAIL-induced apoptosis seemed to be due to activation of PKC and varying levels of PKC
isoenzymes in different
melanoma cell lines. PEP005-mediated enhancement of apoptosis seemed to be associated with low expression of the PKCepsilon
isoform. These results indicate that
PEP005 may enhance or inhibit sensitivity of
melanoma to treatments associated with TRAIL-induced apoptosis depending on the PKC
isoform content of
melanoma cells.