title: Some phorbol esters might partially resemble bryostatin 1 in their actions on LNCaP prostate cancer cells and U937 leukemia cells.
abstract: 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.
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255, USA.
authors.forename: Noemi
authors.initials: N
authors.lastname: Kedei
authors.forename: Emanuel
authors.initials: E
authors.lastname: Lubart
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lewin
authors.forename: Andrea
authors.initials: A
authors.lastname: Telek
authors.forename: Langston
authors.initials: L
authors.lastname: Lim
authors.forename: Poonam
authors.initials: P
authors.lastname: Mannan
authors.forename: Susan H
authors.initials: SH
authors.lastname: Garfield
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Kraft
authors.forename: Gary E
authors.initials: GE
authors.lastname: Keck
authors.forename: Sofiya
authors.initials: S
authors.lastname: Kolusheva
authors.forename: Raz
authors.initials: R
authors.lastname: Jelinek
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D054713:Bryostatins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000473:pathology; D008297:Male; D015394:Molecular Structure; D010703:Phorbol Esters / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D054713:Bryostatins; D010703:Phorbol Esters; C046785:bryostatin 1