carnosol and Cachexia

Cancer cachexia is a systemic metabolic disorder syndrome characterized by severe wasting of muscle and adipose tissues while is lack of effective therapeutic approaches. Carnosol (CS) was found in our previous study to exhibit ameliorating effects on cancer cachexia. In the present study, we designed and synthesized 49 CS analogues by structural modification of CS. Results of activity screening revealed that, among the analogues, WK-63 exhibited better effects than CS in ameliorating atrophy of C2C12 myotubes induced by conditioned medium of C26 tumor cells. WK-63 could also dose-dependently alleviate adipocyte lipolysis of mature 3 T3-L1 cells induced by C26 tumor cell conditioned medium. WK-63 alleviated myotube atrophy by inhibiting Nuclear Factor kappa-B (NF-κB) and activating the Protein Kinase B (AKT) signaling pathway, and also alleviated fat loss by inhibiting NF-κB and Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathways. Results of pharmacokinetic (PK) assay showed that, compared with other analogues, WK-63 exhibited longer half-life (T

Topics: Adipocytes; AMP-Activated Protein Kinases; Animals; Atrophy; Cachexia; Culture Media, Conditioned; Mice; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; Neoplasms; NF-kappa B; Proto-Oncogene Proteins c-akt

Cancer-derived exosomes are involved in the development of cancer cachexia. Carnosol, which exhibited ameliorating effects on cancer cachexia of C26 tumour-bearing mice in our previous study, alleviated atrophy of C2C12 myotubes induced by exosomes of C26 tumour cells in the present study. MiR-183-5p was found to be rich in C26 cells and C26 exosomes, and miR-183-5p mimic could directly induce atrophy of C2C12 myotubes. Carnosol at 5 to 20 μM could dose-dependently ameliorate the myotube atrophy induced by miR-183-5p. Four and a half LIM domain protein 1 (FHL1) was shown to be the direct target of miR-183-5p. Increase in myostatin, p-Smad3, MuRF-1, Atrogin-1, HIF-1α and p-STAT3 and decrease in mitochondrial respiration were also induced by miR-183-5p mimic in C2C12 myotubes. Carnosol could not affect the decrease in FHL-1 and the activation of STAT3 pathway but could significantly alleviate the increase in myostatin, p-Smad3, MuRF-1, Atrogin-1 and the decrease in mitochondrial respiration induced by miR-183-5p. The protective effects of carnosol on myotubes against atrophy of C2C12 myotubes induced by miR-183-5p, based on both its inhibiting effects on MuRF-1 and Atrogin-1-mediated protein degradation and its ability of keeping the mitochondrial respiration, might contribute to its ameliorating effects on cancer cachexia.

Topics: Abietanes; Animals; Atrophy; Cachexia; Cell Line, Tumor; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins; Mice; MicroRNAs; Muscle Fibers, Skeletal; Muscle Proteins; Myostatin; Neoplasms

Cancer cachexia is a multifactorial debilitating syndrome that directly accounts for more than 20% of cancer deaths while there is no effective therapeutic approach for treatment of cancer cachexia. Carnosol (CS) is a bioactive diterpene compound present in Lamiaceae spp., which has been demonstrated to have antioxidant, anti-inflammatory, and anticancer properties. But its effects on cancer cachexia and the possible mechanism remain a mystery.. The in vitro cell models of C2C12 myotube atrophy and 3T3-L1 mature adipocyte lipolysis were used to check the activities of CS and its synthesized analogues. C26 tumour-bearing BALB/c mice were applied as the animal model to examine their therapeutic effects on cancer cachexia in vivo. Levels of related signal proteins in both in vitro and in vivo experiments were examined using western blotting to study the possible mechanisms.. Carnosol and its analogues [dimethyl-carnosol (DCS) and dimethyl-carnosol-D6 (DCSD)] alleviated myotube atrophy of C2C12 myotubes and lipolysis of 3T3-L1 adipocytes in vitro. Interestingly, CS and its analogues exhibited stronger inhibitive effects on muscle atrophy induced by tumour necrosis factor-α (TNF-α) (CS, P < 0.001; DCS, P < 0.001; DCSD, P < 0.001) in C2C12 myoblasts than on muscle atrophy induced by IL-6 (CS, P < 0.05; DCS, P = 0.08; DCSD, P < 0.05). In a C26 tumour-bearing mice model, administration of CS or its analogue DCSD significantly prevented body weight loss without affecting tumour size. At the end of the experiment, the body weight of mice treated with CS and DCSD was significantly increased by 11.09% (P < 0.01) and 11.38% (P < 0.01) compared with that of the C26 model group. CS and DCSD also improved the weight loss of epididymal adipose tissue in C26 model mice by 176.6% (P < 0.01) and 48.2% (P < 0.05) increase, respectively. CS and DCSD treatment partly preserved gastrocnemius myofibres cross-sectional area. CS treatment decreased the serum level of TNF-α (-95.02%, P < 0.01) but not IL-6 in C26 tumour-bearing mice. Inhibition on NF-κB and activation of Akt signalling pathway were involved in the ameliorating effects of CS and its analogues on muscle wasting both in vitro and in vivo. CS and its analogues also alleviated adipose tissue loss by inhibiting NF-κB and AMPK signalling pathways both in vitro and in vivo.. CS and its analogues exhibited anticachexia effects mainly by inhibiting TNF-α/NF-κB pathway and decreasing muscle and adipose tissue loss. CS and its analogues might be promising drug candidates for the treatment of cancer cachexia.

Topics: Abietanes; Animals; Cachexia; Lipolysis; Mice; Mice, Inbred BALB C; Muscular Atrophy; Neoplasms