Investigation of extrinsic and intrinsic apoptosis pathways of new clerodane diterpenoids in human prostate cancer PC-3 cells
Journal
European Journal of Pharmacology
Journal Volume
503
Journal Issue
44199
Pages
17-24
Date Issued
2004
Author(s)
Abstract
In our continuing search to discover bioactive compounds from natural products, we isolated six new clerodane diterpenes, caseamembrins A to F, from Casearia membranacea and examined their antiproliferative activities in human hormone-resistant prostate cancer PC-3 cells. All of these compounds displayed effective antiproliferative activity using sulforhodamine B assays and induced cell apoptosis by a terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL)-reaction technique. The data demonstrated that caseamembrin C was the most effective compound among these clerodane diterpenoids. Caseamembrin C induced down-regulation of Bcl-2 and Bcl-xL expression, while up-regulation of proapoptotic protein Mcl-1S (short chain), suggesting that these Bcl-2 family member proteins may play a role on arbitrating the apoptotic cell death. Caseamembrin C also induced the up-regulation of Fas ligand (FasL) expression, cleavage and activation of caspase-8 and caspase-9, Bid cleavage and activation of executor caspase-3. However, z-IETD-FMK (Z-Ile-Glu-Thr-Asp-fluoromethyl ketone, a selective caspase-8 inhibitor) almost completely inhibited caseamembrin C-induced Bid cleavage without any modification of caspase-9 activation, indicating that the extrinsic pathway of FasL/caspase-8/Bid cascade only played a minor role in the apoptotic signaling. Taken together, it is suggested that caseamembrin C-induced apoptosis is predominantly through the activation of intrinsic apoptosis pathways by causing the down-regulation of Bcl-2 and Bcl-xL expression, up-regulation of Mcl-1S protein and activation of caspase-9 and caspase-3. ? 2004 Elsevier B.V. All rights reserved.
SDGs
Other Subjects
benzyloxycarbonylisoleucylglutamylthreonylaspartyl fluoromethyl ketone; caseamembrin a; caseamembrin b; caseamembrin c; caseamembrin d; caseamembrin e; caseamembrin f; caspase 3; caspase 8; caspase 8 inhibitor; caspase 9; clerodane derivative; diterpenoid; FAS ligand; protein bcl 2; protein bcl x; protein Bid; protein mcl 1; sulforhodamine B; unclassified drug; antineoplastic activity; apoptosis; article; cancer cell culture; Casearia; Casearia membranacea; cell proliferation; controlled study; down regulation; drug mechanism; enzyme activation; enzyme degradation; human; human cell; nick end labeling; priority journal; prostate cancer; protein degradation; protein expression; protein family; Apoptosis; Blotting, Western; Caspases; Cell Line, Tumor; Cell Proliferation; Coloring Agents; Diterpenes; Diterpenes, Clerodane; Enzyme Activation; Fas Ligand Protein; Genes, bcl-2; Humans; In Situ Nick-End Labeling; Male; Membrane Glycoproteins; Neoplasm Proteins; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Rhodamines; Signal Transduction; Tetrazolium Salts; Thiazoles
Type
journal article