PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC

Abstract

Ingenol 3-angelate (PEP005) is a selective small molecule activator of protein kinase C (PKC) extracted from the plant Euphorbia peplus, whose sap has been used as a traditional medicine for the treatment of skin conditions including warts and cancer. We report here that PEP005 also has potent antileukemic effects, inducing apoptosis in myeloid leukemia cell lines and primary acute myeloid leukemia (AML) cells at nanomolar concentrations. Of importance, PEP005 did not induce apoptosis in normal CD34 ؉ cord blood myeloblasts at up to 2-log concentrations higher than those required to induce cell death in primary AML cells. The effects of PEP005 were PKC dependent, and PEP005 efficacy correlated with expression of PKC-delta. The delta isoform of PKC plays a key role in apoptosis and is therefore a rational potential target for antileukemic therapies. Transfection of KG1a leukemia cells, which did not express PKC-delta or respond to PEP005, with enhanced green fluorescent protein (EGFP)-PKC-delta restored sensitivity to induction of apoptosis by PEP005. Our data therefore suggest that activation of PKC-delta provides a novel approach for treatment of acute myeloid leukemia and that screening for PKC-delta expression may identify patients for potential responsiveness to PEP005. (Blood. 2005;106:1362-1368)

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

“…Studies that evaluated the activity of PEP005 as a topical agent for human and mouse xenografts have shown that the predominant mechanism of cell death is necrosis (Ogbourne et al, 2004) and in some melanoma cell lines apoptosis was observed (Gillespie et al, 2004). The capacity of PEP005 to induce apoptosis was further confirmed using leukaemia cancer cells (Hampson et al, 2005). In addition, PEP005 induced cell senescence (Cozzi et al, 2006).…”

“…In previously published studies, PEP005 displayed antiproliferative effects in several human cancer cell lines (Gillespie et al, 2004;Ogbourne et al, 2004;Hampson et al, 2005;Cozzi et al, 2006). Studies that evaluated the activity of PEP005 as a topical agent for human and mouse xenografts have shown that the predominant mechanism of cell death is necrosis (Ogbourne et al, 2004) and in some melanoma cell lines apoptosis was observed (Gillespie et al, 2004).…”

“…PEP005 is currently being developed as a topical treatment for actinic keratoses and basal cell carcinoma (www.cancertrials.gov). In earlier studies, PEP005 Revised 4 August 2008; accepted 6 August 2008 was shown to modulate PKCs by activating PKCd in human myeloid leukaemia cancer cell lines, thereby inducing cellular apoptosis (Hampson et al, 2005) in melanoma models, inducing senescence through PKC-mediated activation of the MAPK pathway (Cozzi et al, 2006) and in colon cancer models, inducing apoptosis through the inhibition of the AKT signalling pathway (Serova et al, 2008). PEP005 appears to be selective for growth inhibition of cancer cells as it does not inhibit the growth of human neonatal fibroblasts (Cozzi et al, 2006) and does not induce apoptosis in normal CD34 þ cord blood myeloblasts (Hampson et al, 2005).…”

Specifying protein kinase C functions in melanoma

“…In melanoma cells, ingenol-3-angelate can induce senescence, apoptosis, or necrosis in a PKC-dependent manner depending on the drug concentration (Cozzi et al, 2006;Gillespie et al, 2004). Ingenol-3-angelate activates the pro-apoptotic PKCd, and its inhibition of melanoma cell growth is associated with induction of p21 and overstimulation of the ERK MAP kinase signaling (Cozzi et al, 2006;Hampson et al, 2005;Mason et al, 2009). In vivo, ingenol-3-angelate is able to penetrate deeply into the skin to cause vascular damage and hemorrhaging owing to its transport by the drug efflux pump P-glycoprotein (Li et al, 2010).…”

“…Ingenol-3-angelate (ingenol mebutate, PEP005) is a PKC activator effective clinically against actinic keratosis, squamous cell carcinoma, and basal cell carcinomas (Anderson et al, 2009;Hampson et al, 2005;Ramsay et al, 2011;Siller et al, 2009Siller et al, , 2010. In melanoma cells, ingenol-3-angelate can induce senescence, apoptosis, or necrosis in a PKC-dependent manner depending on the drug concentration (Cozzi et al, 2006;Gillespie et al, 2004).…”