Abstract
Differentiation of human colonic cancer cells at confluency has been correlated to their increased resistance to chemotherapeutic agents. The aim of this study was to determine whether blocking Caco-2 cell differentiation could sensitize the cells to 5-fluorouracil (5-FU) treatment. We show that in cells at confluency, geraniol (400 μM) prevented the formation of brush-border membranes and inhibited the expression of intestinal hydrolases (sucrase, lactase, alkaline phosphatase). The antiproliferative effect of geraniol (400 μM) together with 5-FU (5 μM) was twice that of 5-FU alone. The cytotoxicity induced by 5-FU was enhanced in the presence of geraniol, as shown by a 50% increase of lactate dehydrogenase release in the culture medium. These effects are related to enhanced intracellular accumulation of 5-FU in the presence of geraniol as shown by a 2-fold increase in intracellular 5-[6-3H]FU (1.5 μCi/ml). It is concluded that geraniol sensitizes colonic cancer cells to 5-FU treatment, by increasing the cytotoxicity of the drug, and that this results from the facilitated transport of 5-FU and the blockade of the morphological and functional differentiation of the cancer cells.
Footnotes
- Abbreviations:
- 5-FU
- 5-fluorouracil
- DMEM
- Dulbecco's modified Eagle's medium
- PBS
- phosphate-buffered saline
- LDH
- lactate dehydrogenase
- FITC
- fluorescein isothiocyanate
- CI
- combination index
- ERK
- extracellular signal-regulated kinase
- Received November 16, 2001.
- Accepted January 16, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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