Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1683-1688 |
| Number of pages | 6 |
| Journal | Oncogene |
| Volume | 24 |
| Issue number | 10 |
| DOIs | |
| State | Published - Mar 3 2005 |
| Externally published | Yes |
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Keywords
- Barrett's associated adenocarcinoma
- Barrett's esophagus
- Flavopiridol
- Mouse model
- p27
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
Cite this
Flavopiridol reduces malignant transformation of the esophageal mucosa in p27 knockout mice. / Lechpammer, Mirna; Xu, Xiangjun; Ellis, F. Henry; Bhattacharaya, Nandita; Shapiro, Geoffrey I.; Loda, Massimo.
In: Oncogene, Vol. 24, No. 10, 03.03.2005, p. 1683-1688.Research output: Contribution to journal › Article
}
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 -