Aranorosin and a novel derivative inhibit the anti-apoptotic functions regulated by Bcl-2.
Bcl-2 is an intracellular membrane protein that prevents cells from undergoing apoptosis in response to various cell-death signals. It negatively regulates mitochondrial outer membrane permeabilization, which is responsible for the release of apoptogenic factors and the subsequent activation of caspases. A microbial metabolite, aranorosin, was identified as an inhibitor of the anti-apoptotic function of Bcl-2. Based on its structure, a more potent derivative, K050, was synthesized. Apoptosis could be induced in a cell line that overexpressed Bcl-2 when cells were treated with an anti-Fas antibody in addition to K050, at sub-micromolar concentrations. Furthermore, K050 inhibited anti-apoptotic functions regulated by Bcl-2, resulting in a Fas-triggered mitochondrial transmembrane potential loss, the activation of caspase-9, and a morphological change to apoptosis. Inhibition of cell-based function of Bcl-2 and its anti-apoptotic effects could serve as useful pharmacological effects. Thus, a novel aranorosin derivative, K050, could be a potent therapeutic agent against Bcl-2-overexpressing human malignancies.
Nakashima
Takayuki
T
Drug Discovery Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan. takayuki.nakashima@kyowa-kirin.co.jp
Tanaka
Rieko
R
Yamashita
Yoshinori
Y
Kanda
Yutaka
Y
Hara
Mitsunobu
M
D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D003513:Cycloheximide / Q000494:pharmacology; D005663:Furans / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019014:fas Receptor / Q000037:antagonists & inhibitors
C533689:4-benzyloxy-N-(3-(2-benzyloxy)acetamido-8-oxo-1-oxaspiro(4,5)deca-6,9-dien-7-yl)benzamide; D005663:Furans; D019253:Proto-Oncogene Proteins c-bcl-2; D013141:Spiro Compounds; D019014:fas Receptor; C058281:aranorosin; D003513:Cycloheximide