Daphnanes diterpenes from the latex of Hura crepitans L. and their PKCζ-dependent anti-proliferative activity on colorectal cancer cells

[Display omitted] •Five new daphnane-type diterpenes were isolated from the latex of Hura crepitans.•Huratoxin and epoxy-huratoxin induced growth inhibition on colorectal cancer cells.•PKCζ is involved in cytostatic and morphological activities of tested daphnanes.•Huratoxin and epoxy-huratoxin inhibit the growth of an ex vivo model of CRC. Hura crepitans L. (Euphorbiaceae) is a thorn-covered tree widespread in South America, Africa and Asia which produces an irritating milky latex containing numerous secondary metabolites, notably daphnane-type diterpenes known as Protein Kinase C activators. Fractionation of a dichloromethane extract of the latex led to the isolation of five new daphnane diterpenes (1–5), along with two known analogs (6–7) including huratoxin. Huratoxin (6) and 4′,5′-epoxyhuratoxin (4) were found to exhibit significant and selective cell growth inhibition against colorectal cancer cell line Caco-2 and primary colorectal cancer cells cultured as colonoids. The underlying mechanism of 4 and 6 was further investigated revealing the involvement of PKCζ in the cytostatic activity.