ABSTRACT
OBJECTIVE: We evaluated whether statins, in view of their anti-inflammatory properties, may effectively prevent the onset or modulate the severity of muscle wasting during cancer cachexia. METHODS: Simvastatin was administered to rats bearing the Yoshida AH-130 ascites hepatoma, a well-studied cytokine-dependent experimental model of cancer cachexia. RESULTS: Quite surprisingly, the drug negatively affected the wasting pattern induced by the AH-130 hepatoma. In fact, the administration of simvastatin to tumor hosts induced a further weight reduction of all the tissues examined except for the soleus, in the absence of significant effects of simvastatin on tumor growth or on food intake. No effects were observed after simvastatin administration in control animals, with the exception of a significant (P < 0.05) reduction in heart weight. CONCLUSIONS: Simvastatin administration, although capable of negatively modulating the inflammatory response, did not prevent muscle wasting in this experimental model of cancer cachexia. Moreover, the further muscle loss observed in simvastatin-treated tumor-bearing animals suggests that a note of caution should be introduced in treating cancer patients with statins in view of the possible occurrence of harmful side effects.
Subject(s)
Anticholesteremic Agents/administration & dosage , Anticholesteremic Agents/adverse effects , Cachexia/prevention & control , Neoplasms, Experimental/complications , Simvastatin/administration & dosage , Animals , Cachexia/etiology , Cholesterol/blood , Cholesterol, HDL/blood , Liver Neoplasms, Experimental , Male , Neoplasm Transplantation , Rats , Rats, Wistar , Triglycerides/blood , Weight Loss/drug effectsABSTRACT
OBJECTIVE: To investigate the state of activation of the ATP-ubiquitin-dependent proteolytic system in the skeletal muscle of gastric cancer patients. SUMMARY BACKGROUND DATA: Muscle wasting in experimental cancer cachexia is frequently associated with hyperactivation of the ATP-dependent ubiquitin-proteasome proteolytic system. Increased muscle ubiquitin mRNA levels have been previously shown in gastric cancer patients, suggesting that this proteolytic system might be modulated also in human cancer. METHODS: Biopsies of the rectus abdominis muscle were obtained intraoperatively from 23 gastric cancer patients and 14 subjects undergoing surgery for benign abdominal diseases, and muscle ubiquitin mRNA expression and proteasome proteolytic activities were assessed. RESULTS: Muscle ubiquitin mRNA was hyperexpressed in gastric cancer patients compared to controls. In parallel, three proteasome proteolytic activities (CTL, chymotrypsin-like; TL, trypsin-like; PGP, peptidyl-glutamyl-peptidase) significantly increased in gastric cancer patients with respect to controls. Advanced tumor stage, poor nutritional status, and age more than 50 years were associated with significantly higher CTL activity but had no influence on TL and PGP activity. CONCLUSIONS: These results confirm the involvement of the ubiquitin-proteasome proteolytic system in the pathogenesis of muscle protein hypercatabolism in cancer cachexia. The observation that perturbations of this pathway in gastric cancer patients occur even before clinical evidence of body wasting supports the thinking that specific pharmacologic and metabolic approaches aimed at counteracting the upregulation of this pathway should be undertaken as early as cancer is diagnosed.
Subject(s)
Cysteine Endopeptidases/metabolism , Multienzyme Complexes/metabolism , Rectus Abdominis/metabolism , Stomach Neoplasms/metabolism , Ubiquitin/metabolism , Biopsy , Chymotrypsin/metabolism , Endopeptidases/metabolism , Female , Gene Expression , Humans , In Vitro Techniques , Male , Middle Aged , Nutritional Status , Proteasome Endopeptidase Complex , RNA, Messenger/metabolism , Stomach Neoplasms/pathology , Trypsin/metabolism , Ubiquitin/genetics , Weight LossABSTRACT
BACKGROUND: Loss of lean body mass is frequently reported in patients with end-stage renal disease (ES-RD). Inadequate nutrient intake, superimposed illnesses, endocrine disorders, uremia and acidosis are some of the potential causes of muscle depletion. Previous reports on experimental models show that lean body mass depletion results from enhancement of muscle tissue protein catabolism, mainly associated with activation of ATP-ubiquitin-dependent proteolysis. Little is known, however, about the affects on this proteolytic system in ESRD patients on maintenance hemodialysis (HD). The present study was designed to investigate the expression of ubiquitin mRNAs in skeletal muscle of patients with ESRD on maintenance HD. METHODS: Biopsies from the rectus abdominis muscle were obtained from eight ESRD patients and from six control subjects undergoing surgery for benign disease. Ubiquitin mRNA levels were measured by Northern blotting analysis. RESULTS: Patients with ESRD had mild metabolic acidosis, as a result of chronic intermittent HD. There were no significant differences between HD patients and controls with regard to the 1.2kb polyubiquitin mRNA species (332.9+/-139 vs 324.2+/-60; ns), but the levels of the 2.4 kb mRNA species were significantly lower in HD patients than in controls (1687+/-542 vs 2529.9+/-325, p=0.01). No correlation was observed between ubiquitin mRNA levels and nutritional parameters and degree of acidosis. CONCLUSIONS: The present study found that the ubiquitin mRNA levels were not increased in the muscle of stable, mildly acidotic hemodialysis patients.
Subject(s)
Cachexia/etiology , Kidney Failure, Chronic/therapy , Muscle, Skeletal/metabolism , Peritoneal Dialysis, Continuous Ambulatory/adverse effects , RNA, Messenger/analysis , Ubiquitin/metabolism , Adult , Biopsy, Needle , Blotting, Northern , Cachexia/diagnosis , Case-Control Studies , Female , Humans , Kidney Failure, Chronic/diagnosis , Male , Middle Aged , Peritoneal Dialysis, Continuous Ambulatory/methods , Probability , Reference Values , Risk Assessment , Sensitivity and Specificity , Statistics, Nonparametric , Ubiquitin/analysisABSTRACT
Bone marrow transplantation (BMT) is a sophisticated procedure consisting of the administration of high-dose chemoradiotherapy followed by intravenous infusion of hemopoietic stem cells to reestablish marrow function when bone marrow is damaged or defective. BMT is used in the treatment of solid tumors, hematologic diseases, and autoimmune disorders. Artificial nutrition, total parenteral nutrition in particular, is provided to patients undergoing BMT to minimize the nutritional consequences of both the conditioning regimens (eg, mucositis of the gastrointestinal tract) and complications resulting from the procedure (eg, graft versus host disease and venoocclusive disease of the liver). Although artificial nutrition is now recognized as the standard of care for BMT patients, defined guidelines for the use of artificial nutrition in this clinical setting are lacking. During the past 2 decades, artificial nutrition in BMT patients has moved from simple supportive care to adjunctive therapy because of the possible benefits, not strictly nutritional, of specialized nutritional intervention. Although data exist documenting the beneficial role of special nutrients, such as lipids and glutamine, in the management of BMT recipients, the results obtained to date are controversial. The reasons for this controversy may reside in the heterogeneity of the patients studied and of the study designs. This review focuses on the need to correctly identify the different patterns of BMT to achieve reproducible and reliable data, which may in turn be used to devise precise guidelines for the use of specialized artificial nutrition in BMT patients.
