Abstract
Skeletal muscle atrophy is a critical feature of cancer-induced cachexia, caused by pro-cachectic factors secreted by host cells and tumor cells. Therefore, blockade of these factors has considered a reasonable target for pharmacological and nutritional interventions to prevent skeletal muscle loss under cancer-induced cachexia. Citrus unshiu peel (CUP) has been used for treating the common cold, dyspepsia, and bronchial discomfort and reported to have pharmacological activities against inflammation, allergy, diabetes, and viral infection. In the present study, we observed that daily oral administration of water extract of CUP (WCUP) to male BALB/c mice bearing CT-26 adenocarcinoma remarkably reduced the losses in final body weight, carcass weight, gastrocnemius muscle, epididymal adipose tissue, and hemoglobin (Hb), compared with saline treatment. The levels of serum IL-6 and muscle-specific E3 ligases elevated by tumor burden were also considerably reduced by WCUP administration. In an in vitro experiment, WCUP efficiently suppressed the production of pro-cachectic cytokines in immune cells as well as cancer cells. In addition, WCUP treatment attenuated C2C12 skeletal muscle cell atrophy caused by cancer cells. These findings collectively suggest that WCUP is beneficial as a nutritional supplement for the management of cancer patients with severe weight loss.
Highlights
Several medical trials on the treatment of cancer cachexia have been performed using synthetic drugs that can stimulate appetite, suppress systemic inflammation, and inhibit tumor-induced protein degradation; they are limited due to the unwanted side effects and low in vivo efficacy
Cancer cachexia is a complex syndrome characterized by anorexia, loss of skeletal muscle and adipose tissue, and involuntary weight loss despite a nutritional supply, and it is closely correlated with high mortality and poor prognosis in cancer patients[17]
Tumor growth was not suppressed by water extract of CUP (WCUP) administration, and tumor weights were similar among control, 250 mg/kg WCUP-treated, and 500 mg/kg WCUP-treated mice at 3.58 ± 0.91, 3.41 ± 0.97, and 3.53 ± 0.92, respectively (Fig. 1C,D)
Summary
Several medical trials on the treatment of cancer cachexia have been performed using synthetic drugs that can stimulate appetite, suppress systemic inflammation, and inhibit tumor-induced protein degradation; they are limited due to the unwanted side effects and low in vivo efficacy. Medroxyprogesterone acetate (MPA) has been widely used as a supportive therapy for patients with cancer- or acquired immune deficiency syndrome-related cachexia, acting as an appetite stimulant. Finding novel agents that efficiently prevent and/or treat cancer-induced cachexia with minimal adverse effects is very important to improve the prognosis of cancer therapy, the survival time, and QoL of cancer patients. Citrus unshiu peel (CUP) has been reported to possess potent anti-inflammatory, anti-oxidant, anti-diabetic, anti-bacterial, and anti-allergic activities[20,21,22]. We aimed to investigate whether water extract of CUP (WCUP) alleviates cancer-induced cachexia symptoms in mice bearing CT-26 adenocarcinoma, including losses in body weight, skeletal muscle, and fat mass. Using the J774A.1 murine macrophage cell line and the C2C12 murine myoblast cell line, the effects and in vitro mechanism of WCUP on the production of pro-cachectic cytokines and muscle atrophy were investigated in detail
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