Anti-interleukin-6 receptor antibody prevents muscle atrophy in colon-26 adenocarcinoma-bearing mice with modulation of lysosomal and ATP-ubiquitin-dependent proteolytic pathways

Abstract

Progression of skeletal muscle atrophy is one of the characteristic features in cancer patients. Interleukin-6 (IL-6) has been reported to be responsible for the loss of lean body mass during cancer cachexia in colon-26 adenocarcinoma (C-26)-bearing mice. This study was carried out to elucidate the intracellular proteolytic pathways operating in skeletal muscle in C-26-bearing mice, and to examine the effect of anti IL-6 receptor antibody on muscle atrophy. On day I 7 after tumor inoculation, trocnemius muscle weight of C-26-bearing mice had the sign' I F = icantly decreased to 69% of that of the pair-fed control mice. This weight loss occurred in association with increases in the mRNA levels of cathepsins B and L, poly-ubiquitin (Ub) and the subunits of proteasomes in the muscles. Furthermore, enzymatic activiky of cathepsin B+L in the muscles also increased to 119% of the control. The administration of antimurine IL-6 receptor antibody to C-26-bearing mice reduced the weight loss of the gastrocnemius muscles to 84% of that of the control mice, whose enzymatic activity of cathepsin B+L and mRNA levels of cathepsin L and poly-Ub were significantly suppressed compared with those of the C-26-bearing mice. Our data indicate that both the lysosomal cathepsin pathway and the ATP-dependent proteolytic pathway might be invoked in the muscle atrophy of C-26-bearing mice. The results also suggest that anti IL-6 receptor antibody could be a potential therapeutic agent against muscle atrophy in cancer cachexia by inhibiting these proteolytic systems.o 1996 Wiley-Liss, Inc.Cachexia is a characteristic syndrome observed in cancer patients; it reduces the response to chemotherapy and diminishes the chance of success for curative surgical treatment. If the progression of muscle wasting seen in malignant neoplastic diseases could be prevented, it would be of clinical importance in terms of improving the prognosis and the quality of life of patients. In cancer cachexia the host suffers from alterations in the metabolism of proteins and amino acids. These changes are characterized by a decrease in protein synthesis and an increase in protein degradation in skeletal muscle (Smith and Tisdale, 1993); the precise mechanism remains unknown, however.Skeletal muscle contains 3 major proteolytic pathways: lysosomal cathepsins, cytosolic Ca?+-dependent proteases (calpain), and the ATP-ubiquitin (Ub)-dependent system. Increases in the mRNA levels of poly-Ub and in the subunits (Llovera et al., 1994). It has thus been concluded that the ATP-Ub-dependent proteolytic pathway is most responsible for the muscle protein degradation seen in the tumor-bearing state. Studies from our laboratory on interleukin-6 (IL-6) transgenic mice revealed that IL-6 is a potent factor that induces muscle atrophy and that it can modulate not only the ATP-Ub-dependent pathway but also the lysosomal cathepsin systems (Tsujinaka et al., 1996).Murine colon-26 adenocarcinoma (C-26) is an undiffcrentiated carcinoma induced by a carcinogen, N-nitroso-Nmethylurethane. ...

Anticachectic effects of the natural herb Coptidis rhizoma and berberine on mice bearing colon 26/clone 20 adenocarcinoma

“…4 In agreement with this finding, we observed that administration of C. rhizoma prevented loss of gastrocnemius muscle in colon 26/clone 20 -bearing mice and decreased IL-6 levels. Tisdale 1 proposed that IL-6 may be a marker rather than an actual mediator of cancer cachexia since direct administration of this cytokine to experimental animals failed to induce cachexia and Hussey et al 22 observed a relation between proteolysis-inducing factor (PIF) and cachexia in colon 26/clone 20 -transplanted mice.…”

“…1,2 IL-6, a mediator produced by tumors or the host as a result of tumor-host interaction, is considered to play an important role in cancer-induced cachexia, suggesting that downregulation of IL-6 levels may improve cachexia or malnutrition in cancer patients. [3][4][5][6] Indeed, an anti-IL-6 receptor antibody has been shown to prevent cancer-induced cachexia in a rodent model. 4 Also, medroxyprogesterone acetate (MPA), a synthetic progesterone derivative, has anticachectic activity, likely due in part to the suppression of IL-6 secretion from tumor cells.…”

“…[3][4][5][6] Indeed, an anti-IL-6 receptor antibody has been shown to prevent cancer-induced cachexia in a rodent model. 4 Also, medroxyprogesterone acetate (MPA), a synthetic progesterone derivative, has anticachectic activity, likely due in part to the suppression of IL-6 secretion from tumor cells. 7 Thus, blockade of IL-6 function might be a useful intervention for the treatment of cachectic patients.…”

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

“…When placed in mice, the C26 adenocarcinoma cell line form tumors which secrete proinflammatory cytokines. IL-6 was initially identified as a prominent player in C26-induced cachexia using anti-IL-6 antibodies, but later studies also identified TNFα and IL-1 [32,76], paralleling human cancer cachexia [17]. While all these cytokines interact with their own unique receptors on striated muscle, each receptor converges on the activation of the transcription factor NF-κB to induce skeletal muscle atrophy.…”

“…Anecdotally, the use of α-3 omega fatty acids (eicosapentaenoic acid) [52] and thalidomide (potent anti-TNF activity) have been reported [48]. Experimentally, glucocorticoids, aspirin [63], indomethacin [35,79], methotrexate [60], and celecoxib [23], all have been shown to have some efficacy, which are believed to be effective, in part, due to their ability to inhibit NF-ĸB activity [10,32,73,78]. However, these agents are neither potent nor selective for the NF-ĸB pathway.…”