Flavopiridol reduces malignant transformation of the esophageal mucosa in p27 knockout mice.
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 downregulation 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.
Lechpammer
Mirna
M
Department of Medical Oncology, Dana-Farber Cancer Institute, D740 44 Binney Street, Boston, MA 02115, USA.
Xu
Xiangjun
X
Ellis
F Henry
FH
Bhattacharaya
Nandita
N
Shapiro
Geoffrey I
GI
Loda
Massimo
M
D000230:Adenocarcinoma / Q000517:prevention & control; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001471:Barrett Esophagus / Q000517:prevention & control; D002294:Carcinoma, Squamous Cell / Q000517:prevention & control; D018797:Cell Cycle Proteins / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004938:Esophageal Neoplasms / Q000517:prevention & control*; D005419:Flavonoids / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D016588:Anticarcinogenic Agents; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D005419:Flavonoids; D010880:Piperidines; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C077990:alvocidib