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Flavopiridol increases sensitization to gemcitabine in human gastrointestinal cancer cell lines and correlates with down-regulation of ribonucleotide reductase M2 subunit.

Abstract
As a single agent, gemcitabine (2',2'-difluorodeoxycytidine) has shown minimal activity against gastrointestinal malignancies with only a modest improvement in survival in patients with pancreatic cancer. Recently, gemcitabine resistance has been associated with the up-regulation of mRNA and protein levels of the ribonucleotide reductase M2 subunit (RR-M2), a rate-limiting enzyme in DNA synthesis that is cell cycle regulated. In this study we show that flavopiridol, a cyclin-dependent kinase inhibitor, enhances the induction of apoptosis by gemcitabine in human pancreatic, gastric, and colon cancer cell lines. As determined by quantitative fluorescence microscopy, flavopiridol enhanced gemcitabine-induced apoptosis 10-15-fold in all of the cell lines tested in a sequence-dependent manner. This was confirmed by poly(ADP-ribose) polymerase cleavage and mitochondrial cytochrome c release. Colony formation assays confirmed the apoptotic rates, showing complete suppression of colony formation only after exposure to sequential treatment of G(24)-->F(24). This is associated with suppression of the RR-M2 protein. This appears to be related to down-regulation of E2F-1, a transcription factor that regulates RR-M2 transcription and hypophosphorylation of pRb. The proteasome inhibitor PS-341 could restore the protein levels of E2F-1 in G(24)-->F(24) treatment indicating that E2F-1 down-regulation is attributable to its increased degradation via ubiquitin-proteasome pathway. This also resulted in restoration of RR-M2 mRNA and protein. These results indicate that flavopiridol in gemcitabine-treated cells inhibits parts of the machinery necessary for the transcription induction of RR-M2. Thus, combining flavopiridol with gemcitabine may provide an important and novel new means of enhancing the efficacy of gemcitabine in the treatment of gastrointestinal cancers.
AuthorsC P Jung, M V Motwani, G K Schwartz
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 7 Issue 8 Pg. 2527-36 (Aug 2001) ISSN: 1078-0432 [Print] United States
PMID11489836 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Cyclin E
  • Cytochrome c Group
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Enzyme Inhibitors
  • Flavonoids
  • Multienzyme Complexes
  • Piperidines
  • Protein Subunits
  • RNA, Messenger
  • Retinoblastoma Protein
  • Transcription Factors
  • Deoxycytidine
  • Tritium
  • Cyclin D1
  • alvocidib
  • Ribonucleotide Reductases
  • Poly(ADP-ribose) Polymerases
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Thymidine
  • Gemcitabine
Topics
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Blotting, Western
  • Cell Cycle Proteins (drug effects, metabolism)
  • Cyclin D1 (drug effects, metabolism)
  • Cyclin E (drug effects, metabolism)
  • Cysteine Endopeptidases (drug effects, metabolism)
  • Cytochrome c Group (drug effects, metabolism)
  • DNA-Binding Proteins
  • Deoxycytidine (analogs & derivatives, pharmacology)
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Drug Synergism
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • Enzyme Inhibitors (pharmacology)
  • Flavonoids (pharmacology)
  • Gastrointestinal Neoplasms (drug therapy, enzymology, pathology)
  • Gene Expression Regulation, Enzymologic (drug effects)
  • Humans
  • Mitochondria (drug effects, metabolism)
  • Multienzyme Complexes (drug effects, metabolism)
  • Phosphorylation (drug effects)
  • Piperidines (pharmacology)
  • Poly(ADP-ribose) Polymerases (metabolism)
  • Proteasome Endopeptidase Complex
  • Protein Subunits
  • RNA, Messenger (drug effects, genetics, metabolism)
  • Retinoblastoma Protein (drug effects, metabolism)
  • Ribonucleotide Reductases (antagonists & inhibitors, genetics, metabolism)
  • Thymidine (metabolism)
  • Transcription Factors (drug effects, metabolism)
  • Tritium
  • Tumor Cells, Cultured
  • Tumor Stem Cell Assay
  • Gemcitabine

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