Depression and possible cancer risk due to oxidative DNA damage
Introduction
Depression is the most common psychiatric disorder among patients with cancer. It is well known and documented that cancer patients are likely to have depressive symptoms after a diagnosis of cancer or during the clinical course of cancer (McDaniel et al., 1995, Cella et al., 1989). For example, the prevalence of depression in cancer patients has been reported to range from 1.5% up to 50% at various times in its clinical course (McDaniel et al., 1995). Because of such an association, depression has been considered to have an impact not only on the progression, but also on the initiation, of cancer (Dalton et al., 2002). There have been several prospective studies in which the relationship between depression and cancer initiation was observed; however, results have remained inconclusive (Persky et al., 1987, Hahn and Petitti, 1988, Kaplan and Reynolds, 1988, Bleiker et al., 1996, Penninx et al., 1998, Gallo et al., 2000, Jacobs and Bovasso, 2000).
Certain methodological limitations may have contributed to the conflicting results. First, the time-lag between the time of psychological investigation and the onset of cancer could have affected the results. It is often difficult to confirm whether a stress assessment actually preceded the initiation of cancer, because the transformation of normal cells into clinically apparent malignant cells can take years. Second, whether a single psychological assessment, as is used in most studies (Persky et al., 1987, Hahn and Petitti, 1988, Kaplan and Reynolds, 1988, Bleiker et al., 1996, Gallo et al., 2000), can reflect long-term psychological state is unknown. Penninx and co-workers (1998) highlighted this problem and found that older persons, who suffered from depressive moods over a 6-year period, had a generally increased risk of cancer. Third, many epidemiological studies have focused their attention on the direct relationships between depression and cancer (Persky et al., 1987, Hahn and Petitti, 1988, Kaplan and Reynolds, 1988, Bleiker et al., 1996, Penninx et al., 1998, Gallo et al., 2000, Jacobs and Bovasso, 2000). On the other hand, genetic examination relevant to cancer initiation at the time of psychological assessment is very limited. Glaser, Kiecolt-Glaser, and their associates have investigated stress-related genetic changes and have found that stress was associated with poor DNA repair in X-irradiated lymphocytes of high-distress psychiatric inpatients (Kiecolt-Glaser et al., 1985), the suppression of synthesis of a DNA repair enzyme, methyltransferase, in rats (Glaser et al., 1985), the decrease of interleukin 2 receptor mRNA expression and interleukin 2 production in leukocytes of medical students (Glaser et al., 1990), the inhibition of apoptosis in leukocytes exposed to γ irradiation in medical students (Tomei et al., 1990), and the decrease in mRNA expression of proto oncogenes, c-myc and c-myb, in leukocytes of medical students (Glaser et al., 1993). Examination stress was used as an academic stress model for the medical students. Those pioneers have provided valuable suggestions regarding stress–gene interaction; however, other pathways, particularly carcinogenic genetic alterations under natural and ordinary stress conditions, remain unclear.
Reactive oxygen species (ROSs), produced in the ordinary course of human life, have been shown to possess a potential role in the initiation, promotion, and progression of cancer (Hursting et al., 1999, Cooke et al., 2003). One of the base modifications due to oxidative stress is 8-hydroxydeoxyguanosine (8-OH-dG, 7,8-dihydro-8-oxoguanosine) (Kasai and Nishimura, 1984). It has been reported that this oxidative DNA damage indicates both mutagenesis and carcinogenesis, and has been considered to be useful in estimating cancer risk. Indeed, chemical carcinogens, tumor-promoting agents, and lifestyles, such as smoking and drinking, have been reported to induce the formation of 8-OH-dG in various target tissues (Kasai, 1997, Kasai, 2002), and increased levels of 8-OH-dG were also found in cancerous tissues (Olinski et al., 1992, Inoue et al., 1998). Owing to these findings, the formation of 8-OH-dG seems to be a valuable biomarker to evaluate the possible stress–cancer linkage under natural and ordinary stress conditions. We recently provided the first evidence that human psychological stress can be associated with increased 8-OH-dG levels in peripheral leukocytes of healthy workers, although gender difference was found (Irie et al., 2001, Irie et al., 2002). The 8-OH-dG levels in females were positively associated with negative moods, such as depression, and inadequate stress coping strategies, whereas those in males were positively related to stressful life changes and long working hours. Among these psychological factors, depressive state was most strongly linked to the 8-OH-dG levels. In addition, we suggested that depressive state is related to the 8-OH-dG levels in leukocytes of females, at least possibly via stress-related increase in the number of neutrophils and the 8-OH-dG production from the neutrophils (Irie et al., 2003). However, whether clinical depression is really associated with 8-OH-dG production remains unknown.
The present study aimed to clarify the possible association between clinical depression and the 8-OH-dG levels in peripheral leukocytes. First, we examined the 8-OH-dG levels in patients with depression, and compared them with age- and gender-matched healthy controls. Second, we examined the factors, including depression, which significantly contributed to the 8-OH-dG levels. We also examined them in view of gender difference, since we found a gender difference in the relationships between psychological factors and leukocyte 8-OH-dG levels in our previous study (Irie et al., 2001, Irie et al., 2002, Irie et al., 2003).
Section snippets
Design and subjects
After approval by the ethics committee, subjects were recruited in a certain hospital and a corporation through announcements asking for volunteers to participate in a study concerning depression and cancer risk via oxidative DNA damage. The participants in this study were 30 outpatients (20 males and 10 females) with depression, according to the Diagnostic and Statistical Manual of Mental Disorders, fourth revision (DSM-IV) (American Psychiatric Association, 1994). Sixty age- and
Results
Comparisons of demographic, lifestyle, and psychological variables and 8-OH-dG levels between depressive patients and healthy controls are shown in Table 1. Mann–Whitney U test was used to assess the differences in the number of health practices and the 8-OH-dG levels. The Tension-Anxiety, Depression-Rejection, Anger-Hostility, Fatigue-Inertia, and TMD scores of the POMS and the CES-D score of the patients were significantly higher, whereas the Vigor-Activity score of the POMS was significantly
Discussion
This study showed that the 8-OH-dG levels in patients with depression were significantly higher than those in age- and gender-matched healthy controls, independently of well-known 8-OH-dG-related factors or risk factors for cancer, such as age, smoking, drinking, exercise, and obesity (Kasai, 1997, Kasai, 2002, Levi, 1999). This tendency was found in both genders; however, females, but not males, showed no significant difference in the 8-OH-dG levels between depressive patients and healthy
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (13671040).
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