Tandospirone reduces wasting and improves cardiac function in experimental cancer cachexia
Introduction
Cancer cachexia is a complication occurring at the last stages of the disease. Cachexia is characterized by a minimum of 5% loss of body weight in one year or less in the presence of an underlying disease. Typical symptoms of cachexia are secondary anorexia, fatigue and decreased muscle strength [1]. The prognosis of cachectic cancer patients is very poor and in more than 20% of cases cachexia is considered to be the cause of death rather than the tumor itself [2].
Weight loss in cachexia is due to the reduction of muscle mass accompanied by the loss of fat tissue [1]. However, most research is focused on stopping or reversing muscle wasting. There is general consensus that of the underlying mechanisms of loss of muscle mass is mainly characterized by disbalance of protein synthesis and protein degradation [3].
It is thought that essentially all organs and tissues are targeted by cachexia, but this has not received much attention and the mechanisms underlying these changes are somewhat unclear [4]. It was shown that hearts suffer from atrophy and dysfunction in murine cancer cachexia models [5], [6], [7]. The connection between heart and muscle wasting is not completely understood, but the limited data suggests that molecular markers and signaling pathways to those activated in cachectic skeletal muscle are involved in the atrophy of cardiac tissue [8], [9]. Moreover, treatment with an anti-myostatin compound mainly developed to protect skeletal muscle also preserved cardiac mass [5].
Aside from profound pathophysiological alterations on the molecular level in various tissues, the quality of life of patients with cancer cachexia is of major importance. Pain, unfavorable prognosis and harsh treatment regimes lead to stress, weakness and ultimately depression in this patients population reviewed in [10]. It was shown in both clinical trials and animal models that depression can promote disease progression, metastasis formation, and decreased immune response [11] and may lower the effectiveness of chemotherapy [12]. Furthermore, depression is linked to suppressed appetite, i.e. secondary anorexia common in cancer cachexia [13]. This is attributed to decreased release of serotonin, which further complicates the psychological state of patients. Interestingly, one of the major side effects of antidepressant drugs is the increase in appetite reviewed in [14], which could have positive effects in the treatment of cachectic cancer patients. Particularly, members of azapirone family that act as selective agonists of 5-hydroxytryptamine 1A (5-HT1A) receptor, a serotonin receptor, and show anxiolytic as well as antidepressant effects could be of interest [15].
In this study we investigated the effect of tandospirone (metanopirone) on the development of cancer cachexia and on heart function using the AH-130 Yoshida hepatoma rat model. Tandospirone is a selective 5-HT1A receptor partial agonist (approx. 55–85% intrinsic activity) [16], which is clinically used in Japan and China. Aside from overall body weight and body composition (fat and lean body mass), cardiac function, quality of life markers and survival were assessed.
Section snippets
Study design
Male Wistar Han rats at the age of 8 weeks and approximate weight of approx. 200 g were housed in groups of three or four in our SPF-animal facility at a constant temperature of 22 °C and exposed to a 12 hour light cycle. Rats had free access to food and water. On day 1 the rats were inoculated intraperitoneally with 108 Yoshida hepatoma AH-130 cells. Organs were weighed on day 16 or the day of death if rats had to be sacrificed earlier due to reaching ethical endpoints [17]. In addition, body
Tandospirone reduces wasting in cancer cachexia
The loss of the total body weight in the placebo group reached 27.3 ± 1.2% suggesting the development of severe cachexia (Fig. 1A). This was significantly reduced by 10 mg/kg/d tandospirone to a loss of body weight of 8.3 ± 6.0% (p = 0.0003), but not by 1 mg/kg/d (Fig. 1A). As body wasting consists of the loss of fat as well as lean body mass, body composition was analyzed (Fig. 1B,C). Similar to the overall weight loss, changes in lean mass were similar in placebo and LD groups (26.5 ± 1.6% and 24.7 ±
Discussion
In this study we characterized the effects of an antidepressant, tandospirone, on the development of cancer cachexia, body composition, quality of life markers and cardiac function in the well established Yoshida hepatoma rat model. While the 1 mg/kg/d dose had overall little effect, 10 mg/kg/d tandospirone reduced weight loss, improved body composition, quality of life indicators as well as cardiac function, and most importantly substantially reduced mortality.
Clinical depression has a
Acknowledgments
The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
References (42)
- et al.
Cachexia: a new definition
Clin Nutr
(2008) - et al.
Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival
Cell
(2010) - et al.
NF-kappaB inhibition protects against tumor-induced cardiac atrophy in vivo
Am J Pathol
(2011) - et al.
Stress, depression, the immune system, and cancer
Lancet Oncol
(2004) Depression and appetite
J Psychosom Res
(1977)- et al.
Antidepressants and weight gain
Appetite
(1988) - et al.
Interaction of SM-3997 with serotonin receptors in rat brain
Jpn J Pharmacol
(1988) - et al.
Effects of tandospirone on second messenger systems and neurotransmitter release in the rat brain
Gen Pharmacol
(1995) - et al.
No effects of human ghrelin on cardiac function despite profound effects on body composition in a rat model of heart failure
Int J Cardiol
(2009) - et al.
The role of serotonin in human mood and social interaction. Insight from altered tryptophan levels
Pharmacol Biochem Behav
(2002)
Cancer cachexia, malnutrition, and tissue protein turnover in experimental animals
Arch Biochem Biophys
Cachexia in cancer patients
Nat Rev Cancer
Activation of the ATP–ubiquitin–proteasome pathway in skeletal muscle of cachectic rats bearing a hepatoma
Am J Physiol
Early development of protein metabolic perturbations in the liver and skeletal muscle of tumour-bearing rats. A model system for cancer cachexia
Biochem J
Cardiac alterations in cancer-induced cachexia in mice
Int J Oncol
Tumor necrosis factor-alpha mediates changes in tissue protein turnover in a rat cancer cachexia model
J Clin Invest
Activation of Ca(2 +)-dependent proteolysis in skeletal muscle and heart in cancer cachexia
Br J Cancer
Stress and coping factors influence tumor growth
Science
Social isolation stress impairs the resistance of mice to experimental liver metastasis of murine colon 26-L5 carcinoma cells
Biol Pharm Bull
Inhibition of xanthine oxidase reduces wasting and improves outcome in a rat model of cancer cachexia
Int J Cancer
IGF-1 treatment reduces weight loss and improves outcome in a rat model of cancer cachexia
J Cachexia Sarcopenia Muscle
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