Tandospirone reduces wasting and improves cardiac function in experimental cancer cachexia

摘要

Background Cancer cachexia is thought to be the cause of > 20% of cancer related deaths. Symptoms of cancer cachexia patients include depression and anorexia significantly worsening their quality of life. Moreover, in rodent models of cancer cachexia atrophy of the heart has been shown to impair cardiac function. Here, we characterize the effects of the antidepressant and anxiolytic drug tandospirone on wasting, cardiac function and survival in experimental cancer cachexia. Methods The well-established Yoshida hepatoma rat model was used and tumor-bearing rats were treated with 1 mg/kg/d (LD), 10 mg/kg/d (HD) tandospirone or placebo. Weight, body composition (NMR), cardiac function (echocardiography), activity and food intake were assessed. Noradrenalin and cortisol were measured in plasma and caspase activity in skeletal muscle. Results Ten mg/kg/d tandospirone decreased the loss of body weight (p = 0.0003) compared to placebo animals, mainly due to preservation of muscle mass (p < 0.001), while 1 mg/kg/d tandospirone was not effective. Locomotor activity (p = 0.0007) and food intake (p = 0.0001) were increased by HD tandospirone. The weight (p = 0.0277) and function of heart (left ventricular mass, fractional shortening, stroke volume, ejection fraction, all p < 0.05) were significantly improved. In the HD tandospirone group, plasma levels of noradrenalin and cortisol were significantly reduced by 49% and 52%, respectively, which may have contributed to the lower caspase activity in the gastrocnemius muscle. Most importantly, HD tandospirone significantly improved survival compared to placebo rats (HR: 0.34; 95% CI: 0.13-0.86; p = 0.0495). Conclusion Tandospirone showed significant beneficial effects in the Yoshida hepatoma cancer cachexia model and should be further examined as a prospective drug for this syndrome.