Inhibition of Barret's adenocarcinoma cell growth by simvastatin: involvement of COX-2 and apoptosis-related proteins.
Recent studies demonstrated that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMG-CoAR), called "statins", independently of their well known plasma cholesterol lowering effect, exert favourable influence on a diverse range of physiologic processes including endothelial function, oxidant stress and antitumor effect. A number of epidemiological studies demonstrated that statins may have protective effect against cancer. The role of statins in the prevention and therapy of Barrett's adenocarcinoma (BA) has not been investigated so far. The aim of the present study was to analyze: 1) the impact of HMG-CoAR inhibitor, simvastatin, on human BA cell growth and 2) effect of simvastatin on apoptosis related proteins Bax/Bcl-2 and cyclooxygenase-2. BA cells (OE-19 cells) were incubated with simvastatin (1-30 microM). MTT assay was used to determine the antiproliferative effects. The expression of COX-2, Bax and Bcl-2 was analyzed at mRNA and protein level by quantitative RT-PCR and immunoblot. MTT assay demonstrated a significant dose-dependent inhibition of OE-19 cell growth by simvastatin, which also caused a significant reduction in Bcl-2 expression and an increase in Bax expression. In OE-19 cells, the COX-2 expression was detected and significantly increased by the addition of TNFalpha into the medium, however, this effect was significantly attenuated by simvastatin. Our in vitro data demonstrate that statins possess anticancerogenic properties possibly due to the induction of apoptosis and inhibition of COX-2. Clinical trial are necessary to prove the beneficial effects of statins on cancerogenesis in Barrett's esophagus.
Konturek
P C
PC
First Department of Medicine, University Erlangen-Nurenberg, Erlangen, Germany. peter.konturek@med1.imed.uni-erlangen.de
Burnat
G
G
Hahn
E G
EG
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000503:physiopathology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001471:Barrett Esophagus / Q000150:complications; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D019821:Simvastatin; D051546:Cyclooxygenase 2