Sosiho-tang ameliorates cachexia-related symptoms in mice bearing colon 26 adenocarcinoma by reducing systemic inflammation and muscle loss

AEYUNG KIM, MINJU IM, JIN YEUL

Cachexia accompanied by muscle wasting is a key determinant of poor prognosis in cancer patients and cancer‑related death. Previous studies have demonstrated that inflammatory cytokines such as interleukin‑6 (IL‑6), tumor necrosis factor‑α (TNF‑α), IL‑1 and interferon‑γ (IFN‑γ) secreted from host cells and tumor cells participate in skeletal muscle wasting followed by severe loss of body weight. Therefore, blockade of the inflammatory response is thought to be a logical target for pharmacological and nutritional interventions to preserve skeletal muscle mass under cachectic conditions. Sosiho‑tang (SO; Xiaocharihu‑tang in Chinese and Sho‑saiko‑to in Japanese) is an Oriental herbal medicine that has been used to treat chronic hepatic diseases and to control fever. In recent studies, SO inhibited the production of inflammatory cytokines in lipopolysaccharide (LPS)‑stimulated macrophages, prevented thrombus formation and suppressed cancer progression. However, the anti‑cachectic activity of SO in tumor‑bearing mice has not yet been examined. In the present study, we characterized the effect of SO administration on cancer‑induced cachexia in CT‑26‑bearing mice, and elucidated the anti‑cachectic mechanisms. Daily oral administration of SO at doses of 50 and 100 mg/kg to CT‑26‑bearing mice significantly retarded tumor growth and prevented the loss of final body weight, carcass weight, heart weight, gastrocnemius muscle, and epididymal fat, compared with saline‑treated control mice. In addition, serum IL‑6 levels elevated by cancer were decreased by SO administration. In the J774A.1 macrophage cell line, SO efficiently suppressed LPS‑mediated increases in inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO), and procachectic inflammatory cytokine production through inhibition of nuclear factor‑κB (NF‑κB) and p38 activation. In addition, SO attenuated muscle atrophy caused by cancer cells by affecting myoblast proliferation and differentiation, and C2C12 myotube wasting. Taken together, these results suggest that SO is a safe and useful anti‑cachectic therapy for cancer patients with severe weight loss.