Mirtazapine Inhibits Tumor Growth via Immune Response and Serotonergic System

Abstract

To study the tumor inhibition effect of mirtazapine, a drug for patients with depression, CT26/luc colon carcinoma-bearing animal model was used. BALB/c mice were randomly divided into six groups: two groups without tumors, i.e. wild-type (no drug) and drug (mirtazapine), and four groups with tumors, i.e. never (no drug), always (pre-drug, i.e. drug treatment before tumor inoculation and throughout the experiment), concurrent (simultaneously tumor inoculation and drug treatment throughout the experiment), and after (post-drug, i.e. drug treatment after tumor inoculation and throughout the experiment). The “psychiatric” conditions of mice were observed from the immobility time with tail suspension and spontaneous motor activity post tumor inoculation. Significant increase of serum interlukin-12 (sIL-12) and the inhibition of tumor growth were found in mirtazapine-treated mice (always, concurrent, and after) as compared with that of never. In addition, interferon-γ level and immunocompetent infiltrating CD4+/CD8+ T cells in the tumors of mirtazapine-treated, tumor-bearing mice were significantly higher as compared with that of never. Tumor necrosis factor-α (TNF-α) expressions, on the contrary, are decreased in the mirtazapine-treated, tumor-bearing mice as compared with that of never. Ex vivo autoradiography with [123I]ADAM, a radiopharmaceutical for serotonin transporter, also confirms the similar results. Notably, better survival rates and intervals were also found in mirtazapine-treated mice. These findings, however, were not observed in the immunodeficient mice. Our results suggest that tumor growth inhibition by mirtazapine in CT26/luc colon carcinoma-bearing mice may be due to the alteration of the tumor microenvironment, which involves the activation of the immune response and the recovery of serotonin level.

Gastroprotective activity of mirtazapine, escitalopram and venlafaxine in depressed rats

“…Ranitidine inhibited the production of TNF-α in monocytes stimulated with lipopolysaccharide in vitro (Okajima et al, 2002) and in stomach of rats subjected to pyloric ligation (Sood and Muthuraman, 2009). Mirtazapine was shown to reduce TNF-α expression in tumor-bearing mice (Fang et al, 2012) and to reduce TNF-α in brain of rats parallel to IL-10 up-regulation (Zhu et al, 2008). Venlafaxine was also shown to suppress TNF-α up-regulation and up-regulate IL-10 level in patients and experimental animals (Kubera et al, 2001; Li et al, 2013).…”

Pre-treatment effects of peripheral tumors on brain and behavior: Neuroinflammatory mechanisms in humans and rodents

“…Commonly identified inflammatory mediators include various cytokines, chemokines, and their receptors (e.g., IL-1, TNFα, IL-6, IL-10, IL-12, TGFβ, MIP1α, CXCR4; Candido & Hagemann, 2013; Turrin et al, 2004), prostaglandin E2, NF-κB and STAT3 signaling cascades, and enzymes such as IDO, COX, and iNOS (reviewed in Cesario et al, 2011; Karin et al, 2002; Landskron et al, 2014; Munn & Mellor, 2013; Uyttenhove et al, 2003). Cytokine production in the tumor microenvironment is sometimes significant enough to be detectable in the general circulation of experimental models (Fang et al, 2012; Lamkin et al, 2011; Norden et al, 2014; Uomoto et al, 1998; Yang et al, 2014). However, this detection appears to be dependent upon the type of tumor and the timing of the blood sampling relative to tumor growth, as elevations in circulating cytokines do not necessarily accompany elevations in tumor cytokines, brain cytokines, or behavioral changes in these models (Catalano et al, 2003; Pyter et al, 2009).…”

Improvement of an atypical Kikuchi-Fujimoto disease (KFD) with antidepressant treatment: the first psychiatric approach to a KFD case

“…Besides antidepressants, the inclusion of specific symptoms, inflammatory biomarkers such as C-reactive protein or interleukin 6, and anti-inflammatory agents may help in the development of more personalized antidepressant treatment procedures. Animal studies revealed that tumour growth inhibition by mirtazapine is thought to be due to the alteration of the tumour microenvironment, which includes the activation of the immune response and the recovery of serotonin level [12]. Fluoxetine is found to able to reverse T cell reactivity impairment in vitro by a direct action at clinically relevant doses [8].…”