Ingenol Mebutate (Ingenol 3-angelate)

Ingenol-3-angelate is a hydrophobic diterpene ester that can be isolated from the euphorb E. peplus. It rapidly induces cell death in proliferating keratinocytes through plasma membrane and mitochondrial disruption, although it can also initiate apoptosis in some cancer cell lines (LD₉₀ = ~190 ?M).¹ Secondarily, ingenol-3-angelate causes inflammation due, at least in part, to activation of PKC, leading to antibody-dependent cellular cytotoxicity.^2,3,4 These actions have relevance in diminishing actinic keratosis and, possibly, other cancers of the skin.^5,6

1.Ogbourne, S.M., Suhrbier, A., Jones, B., et al.Antitumor activity of 3-ingenyl angelate: Plasma membrane and mitochondrial disruption and necrotic cell deathCancer Res.64(8)2833-2839(2004) 2.Gillespie, S.K., Zhang, X.D., and Hersey, P.Ingenol 3-angelate induces dual modes of cell death and differentially regulates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in melanoma cellsMol. Cancer Ther.3(12)1651-1658(2004) 3.Li, L., Shukla, S., Lee, A., et al.The skin cancer chemotherapeutic agent ingenol-3-angelate (PEP005) is a substrate for the epidermal multidrug transporter (ABCB1) and targets tumor vasculatureCancer Res.70(11)4509-4519(2010) 4.Hasler, C.M., Acs, G., and Blumberg, P.M.Specific binding to protein kinase C by ingenol and its induction of biological responsesCancer Res.52(1)202-208(1992) 5.Lebwohl, M., Swanson, N., Anderson, L.L., et al.Ingenol mebutate gel for actinic keratosisN. Engl. J. Med.366(11)1010-1019(2012) 6.Micali, G., Lacarrubba, F., Nasca, M.R., et al.Topical pharmacotherapy for skin cancer. Part I. PharmacologyJ. Am. Acad. Dermatol.70(6)965.e961-956.e912(2014)