Phorbol 12-myristate 13-acetate (PMA) and
bryostatin 1 are both potent
protein kinase C (PKC) activators. In LNCaP human
prostate cancer cells, PMA induces
tumor necrosis factor alpha (TNFα) secretion and inhibits proliferation;
bryostatin 1 does not, and indeed blocks the response to PMA. This difference has been attributed to
bryostatin 1 not localizing PKCδ to the plasma membrane. Since
phorbol ester lipophilicity influences PKCδ localization, we have examined in LNCaP cells a series of
phorbol esters and related derivatives spanning some eight logs in lipophilicity (logP) to see if any behave like
bryostatin 1. The compounds showed marked differences in their effects on proliferation and TNFα secretion. For example, maximal responses for TNFα secretion relative to PMA ranged from 97 % for octyl-
indolactam V to 24 % for
phorbol 12,13-dibenzoate. Dose-response curves ranged from monophasic for
indolactam V to markedly biphasic for
sapintoxin D. The divergent patterns of response, however, correlated neither to lipophilicity, to plasma membrane translocation of PKCδ, nor to the ability to interact with model membranes. In U937 human
leukemia cells, a second system in which PMA and
bryostatin 1 have divergent effects, viz. PMA but not
bryostatin 1 inhibits proliferation and induces attachment, all the compounds acted like PMA for proliferation, but several induced a reduced level or a biphasic dose-response curve for attachment. We conclude that active
phorbol esters are not all equivalent. Depending on the system, some might partially resemble
bryostatin 1 in their behavior; this encourages the concept that
bryostatin-like behavior may be obtained from other structural templates.