Attenuation of proteolysis and muscle wasting by curcumin c3 complex in MAC16 colon tumour-bearing mice

Methodist Research Institute, Clarian Health Partners, Indianapolis, IN 46202, USA.
The British journal of nutrition (Impact Factor: 3.34). 05/2009; 102(7):967-75. DOI: 10.1017/S0007114509345250
Source: PubMed

ABSTRACT Muscle wasting or cachexia is caused by accelerated muscle protein breakdown via the ubiquitin-proteasome complex. We investigated the effect of curcumin c3 complex (curcumin c3) on attenuation of muscle proteolysis using in vitro and in vivo models. Our in vitro data indicate that curcumin c3 as low as 0.50 microg/ml was very effective in significantly inhibiting (30 %; P < 0.05) tyrosine release from human skeletal muscle cells, which reached a maximum level of inhibition of 60 % (P < 0.05) at 2.5 microg/ml. Curcumin c3 at 2.5 microg/ml also inhibited chymotrypsin-like 20S proteasome activity in these cells by 25 % (P < 0.05). For in vivo studies, we induced progressive muscle wasting in mice by implanting the MAC16 colon tumour. The in vivo data indicate that low doses of curcumin c3 (100 mg/kg body weight) was able to prevent weight loss in mice bearing MAC16 tumours whereas higher doses of curcumin c3 (250 mg/kg body weight) resulted in approximately 25 % (P < 0.05) weight gain as compared with the placebo-treated animals. Additionally, the effect of curcumin c3 on preventing and/or reversing cachexia was also evident by gains in the weight of the gastrocnemius muscle (30-58 %; P < 0.05) and with the increased size of the muscle fibres (30-65 %; P < 0.05). Furthermore, curcumin inhibited proteasome complex activity and variably reduced expression of muscle-specific ubiquitin ligases: atrogin-1/muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MURF-1). In conclusion, oral curcumin c3 results in the prevention and reversal of weight loss. The data imply that curcumin c3 may be an effective adjuvant therapy against cachexia.

Download full-text


Available from: Rafat Siddiqui, Jun 18, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: cachexia is common in cancer patients, with profound metabolic abnormalities in response to malignant growth of cancer and progressive catabolism of host. Previous studies showed pharmacodynamics efficacy of curcumin in the prevention and treatment of cancer cachexia. However, the metabolic regulation effect is still unknown. Methods: we employed a proton NMR-metabonomics method to investigate the metabolic features of cancer cachexia and the contribution of curcumin to serum metabolites in a mouse model bearing CT26 tumor. Results: curcumin treatment (200 mg per kg per day) resulted in 13.9% less body weight loss and conserved mass of epididymal fat, muscle gastrocnemius and muscle tibialis anterior 91.4%, 11.5%, and 13.7% respectively in cancer cachexia mice. Proton NMR-based metabolomics revealed the altered metabolic profile and found 25 sensitive metabolites associated with cancer cachexia. Moreover, curcumin treatment resulted in metabolic reprogramming including decrease of phenylalanine, alanine, carnosine, carnitine, taurine, S-sulfocysteine, citrate, malate, glucose, and increase of citrulline, valine, isoleucine, methionine, glycine, acetoacetate and lactate. The pathway analysis showed that the main metabolic regulation of curcumin involved the metabolism of valine, leucine and phenylanaline, and synthesis and degradation of ketone bodies. Conclusions: these altered metabolic pathways imply a highly specific metabolism regulation of curcumin and raise the possibility for its therapeutic effect on alleviating cachexia hypermetabolism.
    RSC Advances 01/2015; 5(16). DOI:10.1039/C4RA14128H · 3.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The present study was designed to investigate the gastroprotective, analgesic, and antipyretic effects of curcumin (Cur), the major constituent of turmeric. Acetylsalicylic acid (ASA) was used in this study as a standard drug for comparison. The analgesic activity was measured using the Hot-Plate Test. The antipyretic and antiulcer effects were assessed using yeast-induced pyrexia and gastric ulceration, respectively. Curcumin (100 mg/kg) injected intra-peritoneally 1 hr prior to the Hot-Plate Test showed significant analgesic activity expressed by both parameters: an increase in latency time and a reduction in paw licking as compared to the controls. In the animal model of pyrexia, curcumin (100 mg/kg injected intra-peritoneally) exhibited a significant reduction in the rectal temperature after 1 hr, 2 hrs, 4 hrs, and 5 hrs of treatment, indicating the antipyretic effect of curcumin. Rats with orally administered curcumin (200 mg/kg) did not show any lesions on the inner lining of the stomach after a 16 hr fast, indicating the gastroprotective effects of curcumin as compared to saline- and acetylsalicylic acid-administered rats. The significantly low ulcer index in curcumin-treated rats following starvation highlights the gastroprotective characteristics of curcumin.
    Scientia Pharmaceutica 06/2013; 81(2):549-58. DOI:10.3797/scipharm.1207-17
  • [Show abstract] [Hide abstract]
    ABSTRACT: Anti-oxidant administration aimed to antagonise development and progression of disuse muscle atrophy provided controversial results. Here we investigated the effects of curcumin, a vegetal polyphenol with pleiotropic biological activity, because of its ability to upregulate Grp94 expression in myogenic cells. Grp94 is a sarco-endoplasmic reticulum chaperone, the levels of which decrease significantly in unloaded muscle.Rats were injected intraperitoneally with curcumin and soleus muscle was analysed after 7 days of hindlimb unloading or standard caging. Curcumin administration increased Grp94 protein level about twofold in muscles of ambulatory rats (P < 0.05) and antagonised its decrease in unloaded ones. Treatment countered loss of soleus mass and myofibre cross-sectional area by approximately 30% (P ≤ 0.02) and maintained force-frequency relationship closer to ambulatory levels. Indexes of muscle protein and lipid oxidation, such as protein carbonylation, revealed by Oxyblot, and malondialdheyde, measured with HPLC, were significantly blunted in unloaded treated rats compared to untreated ones (P = 0.01). Mechanistic involvement of Grp94 was suggested by the disruption of curcumin-induced attenuation of myofibre atrophy after transfection with antisense grp94 cDNA and by the drug positive effect on the maintenance of the subsarcolemmal localization of active nNOS molecules, which were displaced to the sarcoplasm by unloading. The absence of additive effects after combined administration of a nNOS inhibitor further supported curcumin interference with this pro-atrophic pathway.In conclusion, curcumin represents an effective and safe tool to upregulate Grp94 muscle levels and to maintain muscle function during unweighting.This article is protected by copyright. All rights reserved
    The Journal of Physiology 04/2014; 592(12). DOI:10.1113/jphysiol.2013.268672 · 4.54 Impact Factor