Anti-cachectic effect of Antrodia cinnamomea extract in lung tumor-bearing mice under chemotherapy.

Meng-Chuan Chen,Wen-Lin Hsu,Tz-Chong Chou

doi:10.18632/oncotarget.24680

Abstract

Skeletal muscle atrophy, the most characteristic feature of cancer cachexia, often occurs in patients with cancer undergoing chemotherapy. Antrodia cinnamomea (AC) a widely used edible medical fungus, exhibits hepatoprotective, anti-inflammatory and anticancer activities. In this study, we investigated whether combined treatment with the ethonolic extract of AC ameliorates cachexia symptoms, especially muscle wasting, in lung tumor-bearing mice treated with chemotherapy. Our results revealed that gemcitabine and cisplatin-induced severe body weight loss and skeletal muscle atrophy in the mice with cancer were greatly attenuated after AC extract administration. The protection may be attributed to the inhibition of skeletal muscle proteolysis by suppressing myostatin and activin release, muscle wasting-related FoxO3/MuRF-1/MAFbx signaling, proteasomal enzyme activity, and pro-inflammatory cytokine production. A significant decrease in insulin-like growth factor 1 (IGF-1) expression and formation was observed in the atrophying muscle of the conventional chemotherapy treatment group (CGC), and this decrease was markedly reversed by AC treatment. Additionally, the anorexia, intestinal injury and dysfunction that occurred in the CGC group were mitigated by AC extract. Taken together, these results demonstrated that the AC extract has a protective effect against chemotherapy-induced muscle atrophy mainly by attenuating muscle proteolysis, pro-inflammatory cytokine production, and anorexia, and activating IGF-1-dependent protein synthesis.

Highlights

Cancer cachexia is characterized by body weight loss, anorexia, fatigue, inflammation and abnormal metabolism, thereby markedly reducing quality of life and limiting the application of conventional therapy such as chemotherapy [1, 2]
Four groups were used in this study: (1) a normal group; (2) cancer group; (3) CGC group: mice treated with a standard diet and an intraperitoneal injection of gemcitabine (1000 mg/m2 per 3 days) and cisplatin (75 mg/m2/week); (4) CGCA group: mice treated with a standard diet plus Antrodia cinnamomea (AC) extract (300 mg/kg/day, p.o.) and an intraperitoneal injection of gemcitabine and cisplatin
Several tumor and host factors play critical roles in triggering muscle atrophy associated with cancer cachexia by activating muscle proteolytic pathways, impairing protein synthesis, or both [19, 20]

Summary

Introduction

Cancer cachexia is characterized by body weight loss, anorexia, fatigue, inflammation and abnormal metabolism, thereby markedly reducing quality of life and limiting the application of conventional therapy such as chemotherapy [1, 2]. Muscle proteolysis www.oncotarget.com is predominately triggered by the ubiquitin proteasome system (UPS). The forkhead box O (FoxO) transcription factor is a key factor for activating the expression of musclespecific ubiquitin conjugating enzymes E3 ligase, F-box (MAFbx)/atrogin-1 and muscle ring finger 1 (MuRF-1). Increased ubiquitinated protein expression and proteasome activity have been observed in atrophying muscle [7]. Mice that are deficient in either MAFbx or MuRF-1 exhibit greater resistance to atrophy [8], suggesting that suppressing the FoxO/MAFbx/MuRF-1/UPS cascade is a promising strategy of preventing the muscle wasting associated with cancer cachexia. The process of cancer cachexia-evoked muscle atrophy is complex and multifactorial; it is mediated by the interplay of tumor factors, host factors, and the interaction between the two [9, 10]

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