title: The synthetic bryostatin analog Merle 23 dissects distinct mechanisms of bryostatin activity in the LNCaP human prostate cancer cell line.
abstract: Bryostatin 1 has attracted considerable attention both as a cancer chemotherapeutic agent and for its unique activity. Although it functions, like phorbol esters, as a potent protein kinase C (PKC) activator, it paradoxically antagonizes many phorbol ester responses in cells. Because of its complex structure, little is known of its structure-function relations. Merle 23 is a synthetic derivative, differing from bryostatin 1 at only four positions. However, in U-937 human leukemia cells, Merle 23 behaves like a phorbol ester and not like bryostatin 1. Here, we characterize the behavior of Merle 23 in the human prostate cancer cell line LNCaP. In this system, bryostatin 1 and phorbol ester have contrasting activities, with the phorbol ester but not bryostatin 1 blocking cell proliferation or tumor necrosis factor alpha secretion, among other responses. We show that Merle 23 displays a highly complex pattern of activity in this system. Depending on the specific biological response or mechanistic change, it was bryostatin-like, phorbol ester-like, intermediate in its behavior, or more effective than either. The pattern of response, moreover, varied depending on the conditions. We conclude that the newly emerging bryostatin derivatives such as Merle 23 provide powerful tools to dissect subsets of bryostatin mechanism and response.
authors: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Noemi
authors: N
authors: Kedei
authors: Andrea
authors: A
authors: Telek
authors: Alexandra
authors: A
authors: Czap
authors: Emanuel S
authors: ES
authors: Lubart
authors: Gabriella
authors: G
authors: Czifra
authors: Dazhi
authors: D
authors: Yang
authors: Jinqiu
authors: J
authors: Chen
authors: Tyler
authors: T
authors: Morrison
authors: Paul K
authors: PK
authors: Goldsmith
authors: Langston
authors: L
authors: Lim
authors: Poonam
authors: P
authors: Mannan
authors: Susan H
authors: SH
authors: Garfield
authors: Matthew B
authors: MB
authors: Kraft
authors: Wei
authors: W
authors: Li
authors: Gary E
authors: GE
authors: Keck
authors: Peter M
authors: PM
authors: Blumberg
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D054713:Bryostatins / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells
chemical_list: D054713:Bryostatins; C559098:Merle 23; D014409:Tumor Necrosis Factor-alpha; C046785:bryostatin 1; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate