TY - JOUR
T1 - Flavopiridol reduces malignant transformation of the esophageal mucosa in p27 knockout mice
AU - Lechpammer, Mirna
AU - Xu, Xiangjun
AU - Ellis, F. Henry
AU - Bhattacharaya, Nandita
AU - Shapiro, Geoffrey I.
AU - Loda, Massimo
PY - 2005/3/3
Y1 - 2005/3/3
N2 - The cyclin-dependent kinase (cdk) inhibitor p27 preferentially inactivates cdk complexes required for progression through the G1/S transition. Loss of p27 is associated with aggressive behavior in a variety of tumors, including Barrett's associated adenocarcinoma (BAA). We have previously shown that gastroduodenal-esophageal reflux (GDER) together with N-methyl-N- benzylnitrosamine (MBN) induces Barrett's esophagus (BE) and malignant transformation of the esophageal mucosa in mice. This process is enhanced in a p27 null background. Here, we show that chronic flavopiridol administration sharply reduced the prevalence of BE in GDER/MBN-treated p27 knockout mice when compared to animals treated with diluent only (7 vs 26%, P = 0.0079). Similarly, flavopiridol reduced the prevalence of BAA (11 vs 32%, P = 0.0098) and overall cancer prevalence (15 vs 60%, P < 0.0001). In addition, appropriate molecular targeting by flavopiridol in tumor cells was confirmed by down-regulation of cyclin D1, a known target of this pan-cdk inhibitor. The results of this study represent the experimental basis for chemoprevention with cdk inhibitors in human BE and BAA.
AB - The cyclin-dependent kinase (cdk) inhibitor p27 preferentially inactivates cdk complexes required for progression through the G1/S transition. Loss of p27 is associated with aggressive behavior in a variety of tumors, including Barrett's associated adenocarcinoma (BAA). We have previously shown that gastroduodenal-esophageal reflux (GDER) together with N-methyl-N- benzylnitrosamine (MBN) induces Barrett's esophagus (BE) and malignant transformation of the esophageal mucosa in mice. This process is enhanced in a p27 null background. Here, we show that chronic flavopiridol administration sharply reduced the prevalence of BE in GDER/MBN-treated p27 knockout mice when compared to animals treated with diluent only (7 vs 26%, P = 0.0079). Similarly, flavopiridol reduced the prevalence of BAA (11 vs 32%, P = 0.0098) and overall cancer prevalence (15 vs 60%, P < 0.0001). In addition, appropriate molecular targeting by flavopiridol in tumor cells was confirmed by down-regulation of cyclin D1, a known target of this pan-cdk inhibitor. The results of this study represent the experimental basis for chemoprevention with cdk inhibitors in human BE and BAA.
KW - Barrett's associated adenocarcinoma
KW - Barrett's esophagus
KW - Flavopiridol
KW - Mouse model
KW - p27
UR - http://www.scopus.com/inward/record.url?scp=14944339606&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=14944339606&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1208375
DO - 10.1038/sj.onc.1208375
M3 - Article
C2 - 15674336
AN - SCOPUS:14944339606
VL - 24
SP - 1683
EP - 1688
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 10
ER -