Low dose docosahexaenoic acid protects normal colonic epithelial cells from araC toxicity

Ming C Cha,Kelly A Meckling,Angela Lin

doi:10.1186/1471-2210-5-7

Abstract

BackgroundThe nucleoside analogue arabinosylcytosine (araC) has been used for many years in the treatment of acute leukemia. Evidence in the literature suggests that araC may inhibit the growth of human colon carcinoma cell lines as well. Because araC action interferes with normal nucleoside metabolism, it is highly toxic to a number of normal cell types including bone marrow and intestinal mucosa cells. Here we investigate whether the omega-3 fatty acid docosahexaenoic acid (DHA) could selectively target araC toxicity toward colonic tumor cells while protecting the normal cells in vitro.ResultsCultures of normal rat colonic epithelial cells (4D/WT) and those transformed by v-src (D/v-src) were supplemented with graded concentrations of DHA or arachidonic acid (AA) alone or in combination with araC. AraC was only 1.6 fold more toxic to D/v-src than 4D/WT in cultures without added fatty acids. Supplementing with as little as 3 μM of either AA or DHA increased araC toxicity by more than 30-fold in the tumorigenic cells. The toxic effect of araC on the normal cells was also increased by the fatty acid supplementation. IC50 values were decreased 1.7 fold by DHA in the 4D/WT cells but a more than 7-fold decrease was observed during AA supplementation. As a result, the therapeutic index of araC (IC50 normal/IC50 tumor) was more than 3-fold higher in the DHA than the AA supplemented cells. The expression of protein kinase C isoform epsilon was decreased in AA alone supplemented D/v-src cultures but in combination with araC decreased only in DHA supplemented 4D/WT cells.ConclusionLow dose DHA supplementation may enhance araC chemotherapy in colon cancer while protecting normal tissues, possibly through control of PKC signalling pathways.

Highlights

The nucleoside analogue arabinosylcytosine has been used for many years in the treatment of acute leukemia
We have previously demonstrated that docosahexaenoic acid (DHA) can enhance araC and doxorubicin toxicity in leukemia cells and araC toxicity in transformed rat fibroblasts in vitro [5,6]
Using the sulforhodamine dye binding assay the IC50 values for arachidonic acid (AA), DHA, and araC were examined in the normal colonic epithelial cell line 4D/WT and in the v-src transformed variant, D/v-src (Table 1.)

Summary

Introduction

The nucleoside analogue arabinosylcytosine (araC) has been used for many years in the treatment of acute leukemia. Evidence in the literature suggests that araC may inhibit the growth of human colon carcinoma cell lines as well. Colorectal cancer is the second most common cause of death among men and women in North America [1]. This disease may evolve from genetic alterations in protooncogenes or tumor suppressor genes. Arabinosylcytosine (araC) has been used for many years in the treatment of acute leukemia. Some later studies have suggested that araC and the related drug gemcitabine may be useful in inhibiting the growth of human colon (page number not for citation purposes)

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