RESUMEN

BACKGROUND: Cancer cachexia is a serious metabolic disorder syndrome that is responsible for the deaths of approximately 30% of patients with cancer, but effective drugs for cancer cachexia are still lacking. Inflammatory cytokines such as TNF-α or IL-6 are involved in the induction of skeletal muscle atrophy and fat depletion in patients with cancer cachexia. PURPOSE: In this study, we assessed the therapeutic effects of the natural compound alantolactone (AL) on cancer cachexia and tried to clarify the mechanisms by which it ameliorates muscle atrophy. METHODS: The C26 tumor-bearing cancer cachexia mouse model was used to evaluate the efficacy of AL in alleviating cancer cachexia in vivo. The levels of IL-6 or TNF-α in mouse serum were detected using ELISA kits. Cultured C2C12 myotubes and 3T3-L1 adipocytes treated with conditioned medium of C26 tumor cells, IL-6 or TNF-α were employed as in vitro cancer cachexia models to examine the effects of AL in vitro. RESULTS: AL (5 or 10 mg/kg, qd, i.p.) protected mice with C26 tumors and cachexia from a loss of body weight and muscle wasting but only slightly ameliorated fat loss. The circulating level of IL-6 but not TNF-α was significantly decreased by AL. AL treatment significantly inhibited STAT3 activation in the gastrocnemius (GAS) muscle of cancer cachexia mice. AL (0.125, 0.25, 0.5 and 1 µM) dose-dependently ameliorated myotube atrophy and STAT3 activation in cultured C2C12 myotubes induced by conditioned medium from C26 tumor cells. AL also ameliorated C2C12 myotube atrophy induced by IL-6 and inhibited IL-6-mediated STAT3 activation. AL exhibited weak effects on ameliorating TNF-α-mediated myotube atrophy and NF-κB activation. Only AL at high doses of more than 5 µM ameliorated lipolysis and STAT3 activation induced in mature 3T3-L1 adipocytes by conditioned medium from C26 tumor cells. CONCLUSIONS: AL significantly ameliorated muscle atrophy in a cancer cachexia model mainly through the inhibition of the STAT3 pathway. AL might be a promising lead compound in the development of drug candidates for cancer cachexia therapy.

Asunto(s)

Caquexia , Neoplasias , Animales , Caquexia/tratamiento farmacológico , Caquexia/etiología , Caquexia/patología , Humanos , Lactonas , Ratones , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/patología , Atrofia Muscular/tratamiento farmacológico , Atrofia Muscular/etiología , Atrofia Muscular/patología , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Factor de Transcripción STAT3 , Sesquiterpenos de Eudesmano , Transducción de Señal

RESUMEN

SiBaoChongCao (SBCC) is a functional food product containing fermentation of Acremonium terricola belonging to the Cordyceps genus. SBCC at 1 and 2 g kg-1 for 20 days exhibited anti-fatigue activities such as increasing exhaustive swimming and running time of mice and increasing the strength of muscle. The increased muscle endurance in SBCC-treated mice might be related to enhancement of muscle cell growth and differentiation and improvement of muscle response to exercise training, as shown by an increase in muscle cross-sectional area and elevation of MHC, MyoD, MyoG and PGC-1α levels. And, SBCC at 1.5 g kg-1 could ameliorate cancer-related cachexia such as ameliorating decrease in body temperature and inhibiting fat tissue atrophy. The anti-cachexia effects of SBCC might be related to inhibition of inflammatory cytokine IL-6 secretion and suppression of over-lipolysis and lipid over-utilization through inhibiting the activation of AMPK and p38 MAPK and down-regulating the level of UCP1.