Characterization of cytotoxic actions of tricyclic antidepressants on human HT29 colon carcinoma cells
Introduction
Tricyclic antidepressants, such as imipramine, desipramine and amitriptyline, are commonly prescribed for depression, and selective serotonin reuptake inhibitors, fluoxetine and paroxetine, are recently introduced as effective drugs to the medication for depressive mood disorders. In such treatments, patients are usually having medication for long period, and hence there is great risk of these drugs inducing unexpected adverse effects during their long-term use. In particular, the question of whether antidepressants can initiate and/or promote tumor growth in patients and experimental animals has been raised, and the clinical and basic studies on a possible connection between antidepressant use and cancer risk have been carried out. Consequently, the case-control studies have suggested that the increased risk of breast cancer may be associated with the use of antidepressants, particularly genotoxic tricyclic antidepressants (Cotterchio et al., 2000, Sharpe et al., 2002). On the contrary, several studies have provided evidence against the association of antidepressant use with cancer risk (Coogan et al., 2000, Dalton et al., 2000, Dublin et al., 2002, Wang et al., 2001, Weiss et al., 1998). On the other hand, preclinical studies have shown that antidepressants have either no effect, stimulatory effect, or inhibitory effect on the growth of tumors implanted in rodents (Abdul et al., 1995, Bendele et al., 1992, Brandes et al., 1992, Freire-Garabal et al., 1998, Lin et al., 1999). Thus, these previous studies have only provided inconsistent or contradictory evidence, and hence the question regarding the association between antidepressant use and cancer risk still remains to be elucidated. More recently, the analyses of scientific reports in oncology and epidemiology have also shown that the link is questionable but deserving of further investigation on their genotoxic actions (see review; Sternbach, 2003).
Cells have been isolated from different-types of tumors originated from various tissues and organs of different species, and widely used as an in vitro model system for the assessment of tumor growth, and hence the cytotoxic actions of various chemicals and natural substances on tumor cells in culture have been studied as a primary screening for their antitumor activities. As such studies, the direct actions of antidepressants on the growth of various tumor cells have recently been examined, and antidepressants have been shown to cause the apoptotic death of malignant tumor cells (Gavrilova-Ruch et al., 2002, Koch et al., 2003, Serafeim et al., 2003, Slamon and Pentreath, 1998, Slamon and Pentreath, 2000, Slamon et al., 2001, Xia et al., 1999, Xia et al., 1998). In contrast, these drugs have been reported to protect tumor cells against the apoptotic death, and also shown to cause either the stimulatory effect or no notable effect on the proliferation of tumor cells in vitro (Li et al., 2003, Li and Luo, 2002, Volpe et al., 2003). These studies have been carefully carried out, and hence it seems possible that their inconsistent results may be mainly attributed to the difference in tumor cell lines used. Then, we anticipate that it is meaningful as a preclinical study to investigate a potential effects of antidepressants on particular tumor using an appropriate cell line.
Since antidepressants are orally administered to depressive patients, it seems conceivable that these drugs may directly contact with epithelial cells or tumor cells in the gastrointestinal tract for long period, thus resulting in the initiation and/or promotion of tumors with a considerably large probability. Previously, tricyclic antidepressants have been shown to cause the stimulation of cell proliferation in rat intestinal crypt epithelium and the promotion of experimental carcinogenesis in rat colon (Iishi et al., 1993, Tutton and Barkla, 1989), and these studies are thought to suggest that the long-term use of antidepressants may be associated somewhat with the initiation of tumors in the gastrointestinal tract. However, the relationship between the antidepressant use and the risk of colorectal tumors has not yet been fully elucidated because of the inconsistent results of clinical and preclinical studies. Even the direct actions of these drugs on tumor cell growth have been still uncertain. Therefore, it seemed necessary to further investigate the effects of antidepressants on tumor cells, particularly the direct actions of these drugs on the growth of colon cancer cells in culture. Then, to obtain a clue to understanding somewhat the contradiction and inconsistency of the experimental results reported previously, we carried out the in vitro model experiments using human HT29 colon carcinoma cells.
Section snippets
Materials
Human HT29 colon adenocarcinoma cells (HTB-38) were obtained from the American Type Culture Collection (Rockville, MD, USA). Antidepressants, neutral red solution, reduced-form glutathione (GSH), N-acetylcysteine (NAC), catalase, rhodamine-123, digitonin, and carbonyl cyanide 3-chlorophenylhydrazone (CCCP) were obtained from Sigma Chemical Co. (St. Louis, MO, USA). TACS Annexin V-FITC Apoptosis Detection Kit was obtained from R&D Systems, Inc. (Minneapolis, MN, USA). Monoclonal mouse anti-human
Cytotoxic actions of antidepressants on HT29 cells
To examine the direct effects of antidepressants on malignant colorectal tumor cells, human HT29 colon carcinoma cells were exposed to these drugs at the concentrations of 50 μM for 24 h, and the cell viability was determined by measuring the uptake of neutral red into these cells. As shown in Fig. 1, the viability of HT29 cells was reduced by exposing to tricyclic antidepressants, such as imipramine, desipramine and amitriptyline. In addition to these tricyclic antidepressants, a selective
Discussion
Direct actions of antidepressants on human HT29 colon carcinoma cells were examined as an in vitro model experiment for investigating their possible influence on the growth of malignant colorectal tumors. Tricyclic antidepressants, such as imipramine, desipramine and amitriptyline, were shown to cause their cytotoxic actions on these cells in culture (Fig. 1). In addition to these tricyclic antidepressants, fluoxetine, one of the selective serotonin reuptake inhibitors, was shown to cause the
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