Cancer Letters

Cancer Letters

Volume 215, Issue 1, 8 November 2004, Pages 53-59
Cancer Letters

Geraniol, a component of plant essential oils, modulates DNA synthesis and potentiates 5-fluorouracil efficacy on human colon tumor xenografts

https://doi.org/10.1016/j.canlet.2004.06.019Get rights and content

Abstract

We investigated on colon cancer cells the effect of geraniol on thymidylate synthase and thymidine kinase expression, two enzymes related to 5-fluorouracil cytotoxicity. The anti-tumoral efficacy of geraniol and 5-fluorouracil were also evaluated on TC-118 human tumors transplanted in Swiss nu/nu mice. Geraniol (150 μM) but not 5-fluorouracil caused a 2-fold reduction of thymidylate synthase and thymidine kinase expression in cancer cells. In nude mice, the combined administration of 5-fluorouracil (20 mg/kg) and geraniol (150 mg/kg) caused a 53% reduction of the tumor volume, whereas a 26% reduction was obtained with geraniol alone, 5-fluorouracil alone showed no effect.

Introduction

For more than 40 years, 5-fluorouracil (5-FU), a potent inhibitor of thymidylate synthase (TS) was the mainstay of colon cancer chemotherapy, despite the low response rate (20–25%) of the tumors to 5-FU treatment [1]. The sensitivity to 5-FU varies between cells within the same tumor, and several factors are presumably involved in the resistance to 5-FU [2]. TS is responsible for de novo synthesis of dTMP [3]. It was shown that variations in TS kinetic parameters (Km, Vo) were the major determinants for the response variability to 5-FU [4]. Thymidine kinase (TK) activity is responsible for thymidine salvage after 5-FU treatment. If reduced, it may also cause a loss of sensitivity [5]. Dihydropyrimidine dehydrogenase activity, the initial and rate-limiting enzyme of 5-FU catabolism, is also a possible source of the variability in the response of the cancer cells to 5-FU [6]. Other factors, such as modifications of membrane permeability and/or alteration of metabolic pathways are probably also involved in 5-FU sensitivity.

Therapeutic strategies have been developed in order to optimize colorectal cancer treatment. Recent studies have shown that the addition of modulating agents, such as folinic acid, CPT-11, or oxaliplatin increase the response rate to 5-FU in advanced colorectal cancer [7]. For example, the response rate was increased by 30% with folinic acid [8]. Further progress will be achieved by the identification of new anti-cancer drugs acting synergistically with 5-FU.

Geraniol, an acyclic dietary monoterpene found in aromatic herb oils, exerts anti-tumor activity against various cancer cells both in vitro and in vivo [9], [10]. We reported that geraniol inhibited Caco-2 cell growth by reducing DNA synthesis leading to a blockade of the cells in the S phase of the cell cycle [11]. In addition we showed that geraniol increased the cytotoxicity of 5-FU and enhanced the uptake of the drug in human colon cancer cell lines [12].

In order to gain more insight into the mechanism involved in the enhanced efficacy of 5-FU in the presence of geraniol, we investigated the effect of geraniol on TS and TK expression since it has been reported that the down regulation of these enzymes is related to enhanced 5-FU cytotoxicity [4].

We hypothesized that the increased cytotoxic effect of 5-FU observed with geraniol may not only be related to a higher cellular uptake of 5-FU favoring the down regulation of TS, but that geraniol may also alter TK expression since it has been suggested that inhibition of TS activity by 5-FU may be effective when TK activity was reduced [13]. The efficacy of the combination treatment with 5-FU and geraniol was tested on human colorectal cancer TC118 xenografts.

Section snippets

Cell culture

Caco-2 and SW620 cells were obtained from the European Collection of Animal Cell Culture (CERDIC, Sophia Antipolis, France) and were cultured in 75-cm2 Falcon flasks containing DMEM and 25 mM glucose supplemented with 10% heat-inactivated horse serum, 100 U/ml penicillin, and 100 μg/ml streptomycin. Cells were incubated at 37 °C in a humidified atmosphere of 5% CO2, and subcultured after trypsinization (0.5% trypsin/2.6 mM EDTA). They were used up to 30–40 passages.

In all experiments, cells were

Effect of geraniol on 5-FU treated Caco-2 and SW620 cells

The effects of geraniol and 5-FU were studied on exponentially growing Caco-2 (Fig. 1A and B) and SW620 cells (Fig. 1C and D). Cells were treated for 8 days with 5-FU and geraniol alone or in combination. In combinations, 5-FU or geraniol were used at their IC30 value: 150 μM for geraniol (Fig. 1A) and 0.25 μM for 5-FU (Fig. 1B) in Caco-2 cells; and 150 μM for geraniol (Fig. 1C) and 0.8 μM for 5-FU in SW620 cells. In both cell lines the number of surviving cells was significantly lower when 5-FU

Discussion

The present study reports that treatment with geraniol at low concentration (IC30) potentiates 5-FU-mediated growth inhibition of human colon cancer cell lines. The two cell lines (Caco-2 and SW620) differed in their sensitivity to 5-FU and responded differently to geraniol and 5-FU alone and to their combination. The association of 5-FU and geraniol produced a synergistic effect in both cell lines. Geraniol acts at least on two different targets involved in the resistance of cancer cell to

Acknowledgements

This work was supported by a grant from Association pour la Recherche sur le Cancer (ARC). The authors are grateful to Dr N. Seiler for advice and critical reading of the manuscript.

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    Numerous reports also convey that geraniol has potentially controlled several cancers [25–27]. Also, geraniol has been demonstrated to make cancer cells more susceptible to popular chemotherapy drugs like 5-fluorouracil (5-FU) and docetaxel [28–30]. Geraniol's therapeutic activities against cancer have significant clinical and translational significance because it is categorized Food and Drug Administration (FDA) of the US provided its generally recognized as safe (GRAS) [31].

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