Induction of erythroleukemia cell adhesion by plant diterpene tumour promoters: a quantitative study and correlation with in vivo activities

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Abstract
A potent tumour promoter on mouse skin, phorbol-9-myristate-9a-acetate, induces certain clones of Friend erythroleukemia cells to become adhesive to the surface of tissue culture dishes, whereas in the absence of this compound, these cells grow in suspension. We have quantitatively tested 20 other phorbol esters and related compounds for this effect. When the results are expressed as the concentrations of compounds which show half-maximum effect on cell adhesion, the decreasing order of potency is: phorbol-9-myristate-9a-acetate (3.6 × 10−10M) ≊ gnilatimacrin > milliamine A ≊ phorbol-9,9a-didecanoate ≊ mezerein ≊ gnidilatin ≊ ingenol-3,20-dibenzoate > phorbolol-9-myristate-9a-acetate > phorbol-9,9a-dibutyrate ≊ phorbol-9,9a-dibenzoate > 4a-O-methyl-phorbol-9-myristate-9a-acetate > phorbol-9-myristate-9a-acetate-3-aldehyde > phorbol-9,9a-diacetate > 2,3-dihydrophorbol-9-myristate-9a-acetate. Phorbol, 4aα-phorbol-9,9a-didecanoate, phorbol-3,9,9a-triacetate, phorbol-9-myristate, phorhol-9-monoacetate and phorbol-9a-monoacetate were inactive in this assay when tested at concentrations as high as 1 μg/ml (10−6M). None of these 20 compounds induced adhesion when they were tested with a variant clone of Friend erythroleukemia cells which is resistant to the induction of adhesion and several other effects of phorbol-myristate-acetate. When the relative potencies of these compounds in the adhesion assay were compared to available in vivo data on tumour promoting activity on mouse skin, there was, in general, a good qualitative correlation. A better but not perfect quantitative correlation was obtained when the results from the adhesion assay were compared with reported inflammatory activity on mouse ear. When several other tumour promoters and cocarcinogens which differ structurally from the phorbol esters and related plant diterpenes were tested, none of these induced adhesion in this assay.