stilbenes and Cachexia

Cancer-associated cachexia (CAC) is the nutrition-independent loss of lean muscle and adipose tissues, and results in reduced chemotherapy effectiveness and increased mortality. Preventing adipose loss is considered a key target in the early stages of cachexia. Lipolysis is considered the central driver of adipose loss in CAC. We recently found that piceatannol, but not its analogue resveratrol, exhibits an inhibitory effect on lipolysis. The objective of this study was to investigate the role of piceatannol in cancer-associated lipolysis and cachexia-induced weight loss. Cancer cell-induced lipolysis in adipocytes was stimulated using cancer-conditioned media (CCM) or co-culture with human pancreatic cancer cells and the cachexia-associated cytokines TNF-α and interleukin-6 in 3T3-L1 adipocytes. C26 colon carcinoma-bearing mice were modeled using CAC

Topics: Adipose Tissue; Animals; Cachexia; Colonic Neoplasms; Culture Media, Conditioned; Cytokines; Lipolysis; Mice; Neoplasms; Polyphenols; Stilbenes; Weight Loss

The abnormalities associated with cancer cachexia include anorexia, weight loss, muscle loss and atrophy, anaemia and alterations in carbohydrate, lipid and protein metabolism. The aim of the present investigation was to examine the anti-wasting effects of some nutraceuticals such as genistein, resveratrol, epigallocatechin gallate and diallyl sulphide (DAS).. The in vitro effects of these nutraceuticals on proteolysis were examined in muscle cell cultures submitted to hyperthermia. The in vivo effects of DAS were also tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma).. Although all the nutraceuticals tested inhibited muscle proteolysis, the most promising effects were related with DAS. In vivo administration of DAS only leads to a small improvement in tibialis muscle and heart weights; however, administration of DAS to healthy animals increased all muscle weights, this being associated with a decreased gene expression of proteolytic systems components.. It may be suggested that DAS could be used to improve muscle mass during healthy conditions.

Topics: Allyl Compounds; Animals; Anorexia; Cachexia; Catechin; Cells, Cultured; Dietary Supplements; Genistein; Male; Muscle, Skeletal; Muscular Atrophy; Neoplasms; Rats; Rats, Wistar; Resveratrol; Stilbenes; Sulfides; Weight Loss

The mechanism by which cancer mediates muscle atrophy has been delineated in the past 3 decades and includes a prominent role of tumor-derived cytokines, such as IL-6, TNFα, and IL-1. These cytokines interact with their cognate receptors on muscle to activate the downstream transcription factor NF-κB and induce sarcomere proteolysis. Experimentally, inhibiting NF-κB signaling largely prevents cancer-induced muscle wasting, indicating its prominent role in muscle atrophy. Resveratrol, a natural phytoalexin found in the skin of grapes, has recently been shown to inhibit NF-κB in cancer cells, which led us to hypothesize that it might have a protective role in cancer cachexia. Therefore, we investigated whether daily oral resveratrol could protect against skeletal muscle loss and cardiac atrophy in an established mouse model. We demonstrate resveratrol inhibits skeletal muscle and cardiac atrophy induced by C26 adenocarcinoma tumors through its inhibition of NF-κB (p65) activity in skeletal muscle and heart. These studies demonstrate for the first time the utility of oral resveratrol therapy to provide clinical benefit in cancer-induced atrophy through the inhibition of NF-κB in muscle. These findings may have application in the treatment of diseases with parallel pathophysiologies such as muscular dystrophy and heart failure.

Topics: Adenocarcinoma; Administration, Oral; Animals; Body Composition; Cachexia; Cell Line, Tumor; Dose-Response Relationship, Drug; Echocardiography; Female; Gene Expression Regulation, Enzymologic; Heart; Mice; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Myocardium; Neoplasm Transplantation; Random Allocation; Resveratrol; RNA, Messenger; Stilbenes; Transcription Factor RelA; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Weight Loss

Topics: Cachexia; Clinical Trials as Topic; Drug Approval; Drug Discovery; Drug Industry; Growth Hormone-Releasing Hormone; Humans; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Receptors, Retinoic Acid; Research; Retinoic Acid Receptor gamma; Stilbenes; Weight Loss

Resveratrol has been reported to have antitumoural effects and recently it has been demonstrated that resveratrol partially blocks skeletal muscle wasting by interfering with NF-kappaB activation. We decided to investigate the potential anti-wasting properties of resveratrol on different models of cancer cachexia in experimental animals.. Incubations of isolated extensor digitorum longus muscles in the presence of 30 microM of resveratrol caused a significant decrease in the rate of protein degradation. However, administration of resveratrol in vivo to both rats bearing the Yoshida AH-130 ascites hepatoma (at the dose of 1 mg/kg body weight) and mice bearing the Lewis lung carcinoma (at two different doses, 5 and 25 mg/kg body weight) had no effect on skeletal muscle mass or body weight in tumour-bearing rodents. In addition, a combination of resveratrol (3 mg/kg body weight) and fish oil was also unable to induce any changes in skeletal muscle weights.. It is therefore concluded from this study that resveratrol is unable to influence muscle mass in vivo and has no potential role as anticachectic agent for the treatment of muscle wasting associated with tumour growth.

Topics: Animals; Body Weight; Cachexia; Carcinoma, Lewis Lung; Disease Models, Animal; Energy Intake; Fish Oils; Male; Mice; Mice, Inbred C57BL; Muscle Proteins; Muscle, Skeletal; Neoplasms, Experimental; NF-kappa B; Organ Size; Random Allocation; Rats; Rats, Wistar; Resveratrol; Sarcoma, Yoshida; Stilbenes

The potential for inhibitors of nuclear factor-kappaB (NF-kappaB) activation to act as inhibitors of muscle protein degradation in cancer cachexia has been evaluated both in vitro and in vivo. Activation of NF-kappaB is important in the induction of proteasome expression and protein degradation by the tumour factor, proteolysis-inducing factor (PIF), since the cell permeable NF-kappaB inhibitor SN50 (18 microM) attenuated the expression of 20S proteasome alpha-subunits, two subunits of the 19S regulator MSS1 and p42, and the ubiquitin-conjugating enzyme, E2(14k), as well as the decrease in myosin expression in murine myotubes. To assess the potential therapeutic benefit of NF-kappaB inhibitors on muscle atrophy in cancer cachexia, two potential inhibitors were employed; curcumin (50 microM) and resveratrol (30 microM). Both agents completely attenuated total protein degradation in murine myotubes at all concentrations of PIF, and attenuated the PIF-induced increase in expression of the ubiquitin-proteasome proteolytic pathway, as determined by the 'chymotrypsin-like' enzyme activity, proteasome subunits and E2(14k). However, curcumin (150 and 300 mg kg(-1)) was ineffective in preventing weight loss and muscle protein degradation in mice bearing the MAC16 tumour, whereas resveratrol (1 mg kg(-1)) significantly attenuated weight loss and protein degradation in skeletal muscle, and produced a significant reduction in NF-kappaB DNA-binding activity. The inactivity of curcumin was probably due to a low bioavailability. These results suggest that agents which inhibit nuclear translocation of NF-kappaB may prove useful for the treatment of muscle wasting in cancer cachexia.

Topics: Animals; Blood Proteins; Cachexia; Cells, Cultured; Chymotrypsin; Curcumin; Electrophoretic Mobility Shift Assay; Enzyme Activation; Enzyme Inhibitors; I-kappa B Proteins; Male; Mice; Mice, Inbred Strains; Muscle Fibers, Skeletal; Muscle, Skeletal; Neoplasms, Experimental; NF-kappa B; NF-KappaB Inhibitor alpha; Proteasome Endopeptidase Complex; Proteoglycans; Resveratrol; Stilbenes; Ubiquitins; Weight Loss