Flavopiridol reduces malignant transformation of the esophageal mucosa in p27 knockout mice

Mirna Lechpammer, Xiangjun Xu, F. Henry Ellis, Nandita Bhattacharaya, Geoffrey I. Shapiro, Massimo Loda

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1683-1688
Number of pages6
JournalOncogene
Volume24
Issue number10
DOIs
StatePublished - Mar 3 2005
Externally publishedYes

Fingerprint

alvocidib
Barrett Esophagus
Cyclin-Dependent Kinases
Knockout Mice
Adenocarcinoma
Gastroesophageal Reflux
Cyclin-Dependent Kinase Inhibitor p27
Neoplasms
Cyclin D1
Chemoprevention
Down-Regulation
Esophageal Mucosa

Keywords

  • Barrett's associated adenocarcinoma
  • Barrett's esophagus
  • Flavopiridol
  • Mouse model
  • p27

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Lechpammer, M., Xu, X., Ellis, F. H., Bhattacharaya, N., Shapiro, G. I., & Loda, M. (2005). Flavopiridol reduces malignant transformation of the esophageal mucosa in p27 knockout mice. Oncogene, 24(10), 1683-1688. https://doi.org/10.1038/sj.onc.1208375

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 journalArticle

Lechpammer, M, Xu, X, Ellis, FH, Bhattacharaya, N, Shapiro, GI & Loda, M 2005, 'Flavopiridol reduces malignant transformation of the esophageal mucosa in p27 knockout mice', Oncogene, vol. 24, no. 10, pp. 1683-1688. https://doi.org/10.1038/sj.onc.1208375
Lechpammer, Mirna ; Xu, Xiangjun ; Ellis, F. Henry ; Bhattacharaya, Nandita ; Shapiro, Geoffrey I. ; Loda, Massimo. / Flavopiridol reduces malignant transformation of the esophageal mucosa in p27 knockout mice. In: Oncogene. 2005 ; Vol. 24, No. 10. pp. 1683-1688.
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