Chinese herbal medicine Sijunzi decoction alleviates liver cancer cachexia through downregulating TGF-β and IGF 1 signaling pathways

Introduction: Liver cancer is the fifth most common type of malignancy in humans and ranked second worldwide in cancer mortality. More than half of cancer patients develop cachexia, a life-threatening condition for which therapeutic options are limited. Cancer cachexia correlates with poor performance status, poor quality of life, and a high mortality rate in cancer patients. Therefore, effective management of cachexia is important but is an unmet medical need. A well-known traditional Chinese medicine recipe Sijunzi decoction (SD) has been used to treat the cachectic condition with demonstrated improvement in the quality of life after chemotherapy administration. However, very little is known about the mechanism underlying the treatment. Thus, the aim of this study was to investigate the anti-cachexia mechanism of SD and provide evidence for the role of SD in the management of cachexia. Methods: Mouse models of cachexia (ascites-type advanced liver cancer) were prepared by intraperitoneal injection of 106 cells/mL H22 mouse hepatoma cells into C57/6 mice. The mice were then divided into 4 groups (n = 15): Group A-negative control (no treatment), Group B-positive control (treated with conventional treatment plan using indomethacin at 0.5 mg/kg plus medroxyprogesterone at 120 mg/kg daily), Group C- treated with low-dose SD (5g/kg, daily), and Group D- treated with high-dose SD (30 g/kg daily). The SD used was composed of Ginseng Radix et Rhizoma, Poria, Atractylodis Macrocephalae Rhizoma, and Glycyrrhizae Radix et Rhizoma with a dosage ratio of 10:9:9:6, respectively. The concentration of the crude drug was prepared at 1.0 g/mL. The treatment was administered for 14 days after which the mice were sacrificed. During the treatment period, food intakes, body weight, ascites volume were monitored on a daily basis. Protein expression of IGF1R, Akt, Foxo3, and TGFβ1 in the liver was examined by Western blotting. Results: We found that SD at high dose significantly improved the body weight and food intake and significantly reduced the volume of ascites when compared with the negative control group A, at the end of the 14 days treatment. The effect of SD on reducing ascites was superior to the conventional treatment group (P < 0.01), some of the key proteins involved in the intracellular signaling pathway of cachexia. Conclusion: High-dose SD can effectively control the key features of liver cancer cachexia in mouse models, with a superior outcome to that treated with currently available treatment. The underlying anti-cachexia mechanism of SD may be related to the downregulation of TGF-β and IGF1 signaling pathway. Potentially SD could be an option for better management of cachexia.