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Current Opinion in Clinical Nutrition... Jul 2005The anorexia-cachexia syndrome is highly prevalent in patients suffering from acute and chronic diseases, including cancer, chronic renal failure and liver cirrhosis.... (Review)
Review
PURPOSE OF REVIEW
The anorexia-cachexia syndrome is highly prevalent in patients suffering from acute and chronic diseases, including cancer, chronic renal failure and liver cirrhosis. Once it has developed, it significantly influences the clinical course of the underlying disease, simultaneously impinging on patients' quality of life. Unfortunately, currently available therapeutic strategies do not appear to greatly impact on patients' morbidity, mortality and quality of life. More effective therapies are needed to promote appetite and food intake, to preserve lean body mass, and to ameliorate patients' psychological distress.
RECENT FINDINGS
Branched-chain amino acids are neutral amino acids with interesting and clinically relevant metabolic effects. Their potential role as antianorexia and anticachexia agents was proposed many years ago, but only recent experimental studies and clinical trials have tested their ability to stimulate food intake and counteract muscle wasting in anorectic, weight-losing patients. By interfering with brain serotonergic activity and by inhibiting the overexpression of critical muscular proteolytic pathways, branched-chain amino acids have been shown to induce beneficial metabolic and clinical effects under different pathological conditions.
SUMMARY
Based on the available data, branched-chain amino acids appear to exert significant antianorectic and anticachectic effects, and their supplementation may represent a viable intervention not only for patients suffering from chronic diseases, but also for those individuals at risk of sarcopenia due to age, immobility or prolonged bed rest, including trauma, orthopedic or neurologic patients.
Topics: Amino Acids, Branched-Chain; Anorexia; Appetite; Body Weight; Cachexia; Energy Intake; Energy Metabolism; Humans; Quality of Life; Research
PubMed: 15930966
DOI: 10.1097/01.mco.0000172581.79266.19 -
Head & Neck Apr 2007Cancer cachexia is a debilitating, wasting condition that affects many cancer patients, including those with head and neck cancer. The overall incidence of cancer... (Review)
Review
BACKGROUND
Cancer cachexia is a debilitating, wasting condition that affects many cancer patients, including those with head and neck cancer. The overall incidence of cancer cachexia is quite high for some types of cancer, and cachexia will be the main cause of death for more than 20% of all cancer patients. This syndrome uniquely challenges patients with head and neck cancer. This article outlines the diagnosis of cancer cachexia, reviews its impact on patient quality of life (QOL) and survival, and updates the reader on potential therapies that may suppress it.
METHODS
A comprehensive literature search was performed using PubMed of the National Library of Medicine, which includes more than 15 million citations back to the 1950s. The Cochrane Library and Google search engine were used as well.
RESULTS
This syndrome differs significantly from starvation, and thus accurate and timely diagnosis is essential. Nutritional therapy alone is insufficient. Current management strategies include corticosteroids and megesterol acetate, in conjunction with nutritional therapy. Future strategies may include nutraceuticals, omega-3 fatty acids, inflammatory antagonists, and other targeted treatments.
CONCLUSIONS
Because cancer cachexia differs significantly from starvation, nutritional supplementation must be used in conjunction with other anti-cachexia agents to reverse the chronic systemic inflammatory state and the effects of circulating tumor-derived factors seen in cachexia. Careful identification of patients at risk and those suffering from this syndrome will lead to better outcomes and treatments. Ultimately, more research is needed to better treat this devastating condition.
Topics: Cachexia; Head and Neck Neoplasms; Humans; Nutritional Support; Quality of Life; Survival Rate
PubMed: 17285641
DOI: 10.1002/hed.20447 -
International Journal of... 1989Experiments were performed to determine the effects of hydrazine sulfate (HS), a potential anti-cachexia agent, on tumor necrosis factor activities (cachectin/TNF) in...
Experiments were performed to determine the effects of hydrazine sulfate (HS), a potential anti-cachexia agent, on tumor necrosis factor activities (cachectin/TNF) in vitro. We present evidence that HS significantly inhibits the lytic activity of TNF on L-929 cells, that HS has no direct effect on TNF itself, and that the minimum amount of time for maximum inhibition of TNF activity to occur after HS treatment is between 1 and 4 h. In addition to HS's effect on the cytolytic activity, we also determined its effect on the antiviral activity of TNF. We found that HS greatly potentiates TNF antiviral activity, while having no significant antiviral activity itself over a range of concentrations, that the potentiation was likely between HS and TNF-induced interferon-B1, and was maximal following 4 and 8 h of treatment with HS. Although the lytic activity of TNF has not been directly correlated with its cachectic activities, these studies provide evidence for an effect of HS on cachectin and its role in the wasting process. Furthermore, a rationale is provided for use of HS in conjunction with TNF for prevention and/or treatment of viral infection.
Topics: Animals; Antiviral Agents; Cachexia; Cells, Cultured; Cytotoxins; Drug Synergism; Hydrazines; Kinetics; Mice; Tumor Necrosis Factor-alpha
PubMed: 2807626
DOI: 10.1016/0192-0561(89)90179-3 -
International Journal of Cancer Nov 2011Loss of adipose tissue, primarily due to increased lipolysis but also to an impairment of adipogenesis, is a key feature of weight loss in cancer cachexia. Because of...
Loss of adipose tissue, primarily due to increased lipolysis but also to an impairment of adipogenesis, is a key feature of weight loss in cancer cachexia. Because of the myriad pathogenic signaling pathways essential for atrophy of adipose tissue, effective therapeutic agents for cachectic adipose loss are lacking and urgently needed. The authors evaluated the effects of YC-1 on adipogenesis of 3T3-L1 preadipocytes, TNF-α- and tumor-cell-induced lipolysis in 3T3-L1 adipocytes, and cachectic weight loss in colon-26 adenocarcinoma-bearing mice because YC-1 has been shown to possess versatile pharmacological actions, including anticancer activity. It was found that YC-1 promotes the differentiation of 3T3-L1 preadipocytes into adipocytes through activation of Akt and extracellular signal-regulated kinase (ERK) signaling pathways as well as activation of several adipogenic mediators, such as peroxisome proliferator-activated receptor γ (PPARγ), insulin receptor α (IRα), insulin receptor substrate-3 (IRS-3) and glucose transporter-4 (GLUT-4). In the in vitro lipolysis models, YC-1 attenuates TNF-α-induced lipolysis of adipocytes by antagonizing TNF-α-mediated activation of ERK and downregulation of perilipin (PLIN). It was also found that YC-1 inhibits colon-26 adenocarcinoma cell-induced lipolysis of 3T3-L1 adipocytes. Moreover, YC-1 effectively rescues cachectic weight loss in colon-26 adenocarcinoma-bearing mice by blocking lipolysis, involving insulin. Taken together the results show that YC-1 with its anticancer and anticachexia talents is highly worth developing as a novel agent for cancer therapy.
Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Antineoplastic Agents; Cachexia; Enzyme Activators; Female; Indazoles; Lipolysis; Mice; Mice, Inbred BALB C; Neoplasms; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 21557215
DOI: 10.1002/ijc.26174 -
Cancer Chemotherapy and Pharmacology Jul 2003The full-scale commercial appearance of antibiotics in the 1950s caused a shift in the nature of lethal diseases from infectious and acute to noninfectious and chronic.... (Review)
Review
The full-scale commercial appearance of antibiotics in the 1950s caused a shift in the nature of lethal diseases from infectious and acute to noninfectious and chronic. In this situation, biological response modifiers (BRMs), which are not based on selective toxicity, could be expected to be useful. Several types of BRM exist, including retinoids, which act directly on cells at the level of gene expression, and thalidomide and related molecules, which modulate the production of various cytokines. We have been engaged in medicinal, chemical, and structural development studies based on these bioactive compounds. Retinoids include all- trans-retinoic acid (ATRA), a major active form of vitamin A (retinol), and its bioisosters, which elicit their biological effects by binding to their nuclear receptors, retinoic acid receptors (RARs). ATRA has been used in differentiation therapy, typically for the treatment of acute promyelocytic leukemia, and the treatment of dermatological diseases. Our structural development studies of retinoids, including computer-assisted molecular design, have yielded class/subtype-selective agonists, synergists, and antagonists of RARs and their partner nuclear receptors, retinoid X receptors. Among them, the benzanilide-type compounds, Am80 and TAC101, are under phase II and I/II clinical studies in Japan and the USA, respectively. Thalidomide is a hypnotic/sedative drug that was withdrawn from the market because of teratogenicity. However, thalidomide has been established to be useful in the treatment of various diseases including cancer. Thalidomide elicits a wide range of pharmacological effects, including anticachexia, anti-tumor-promoting, antiangiogenic, immunosuppressing, antiviral, hypoglycemic, and antimetastatic activities. We have found that thalidomide is a multitarget drug. Hypothetical target events/molecules of thalidomide include tumor necrosis factor-alpha production, nuclear androgen receptor, cyclooxygenases, aminopeptidases, and alpha-glucosidase. Specific and potent compounds for each of these target phenomena/molecules have been prepared by appropriate modification of the thalidomide structure, and are expected to be superior lead compounds for novel immunomodulators, antiangiogenic agents, and anti-tumor-promoting agents.
Topics: Computer Simulation; Drug Design; Models, Chemical; Molecular Structure; Retinoids; Thalidomide
PubMed: 12819930
DOI: 10.1007/s00280-003-0590-3 -
Scientific Reports Jul 2018Persimmon (Diospyros kaki L.) leaves are commonly used in Asia as tea infusion and as an agent in traditional medicine. The present study aims to explore the antitumor...
Persimmon (Diospyros kaki L.) leaves are commonly used in Asia as tea infusion and as an agent in traditional medicine. The present study aims to explore the antitumor and immunomodulatory effects of total flavonoids extract from persimmon leaves (PLF) in H liver tumor-bearing mice. We found that the PLF showed significant inhibition on the liver tumor growth in mice with a tumor inhibition rate of up to 49.35%. In contrast to the severe side effects of cyclophosphamide (CTX), the PLF exhibited anti-cachexia effect and showed no alternation in the body weight and food intake in mice. Moreover, compared with the vehicle control and CTX group, the PLF significantly enhanced the thymus and spleen indices, level of serum interleukin-18 (IL-18), monocyte/macrophage phagocytosis, level of serum hemolysin, and activity of natural killer (NK) cells. This study demonstrated that the PLF could effectively inhibit liver tumor growth in vivo via enhancement of the immune function in mice, and it displayed the potential to be a safe and effective anticancer agent or functional immune-enhancing agent.
Topics: Animals; Antineoplastic Agents, Immunological; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Line, Tumor; Cyclophosphamide; Diospyros; Disease Models, Animal; Drug Screening Assays, Antitumor; Female; Flavonoids; Humans; Killer Cells, Natural; Liver Neoplasms; Macrophages; Male; Mice; Phagocytosis; Plant Extracts; Plant Leaves
PubMed: 30002398
DOI: 10.1038/s41598-018-28440-8 -
Current Opinion in Supportive and... Dec 2007To summarize the latest clinical developments in pharmacological interventions for primary cachexia. (Review)
Review
PURPOSE OF REVIEW
To summarize the latest clinical developments in pharmacological interventions for primary cachexia.
RECENT FINDINGS
New orexigenic interventions that interfere with the central regulation of food intake are expected to be derived from the group of melanocortin receptor antagonists and ghrelin-mimetic agents. Emerging are muscle agents, including ubiquitin-proteasome system inhibitors, antimyostatin drugs, dystrophin, and beta2-adrenergic agonists. Results from anabolic steroids and angiotensin-II inhibitors are awaited. Recent data support insulin tackling fat metabolism. Branched-chain amino acids, N-3 fatty acids and conjugated linoleic acid are nutritional supplements that show potential. Adenosine 5'-triphosphate expands to related compounds (including ubiquinone). No breakthrough has occurred with the use of anti-inflammatory agents. Moreover, nonsteroidal anti-inflammatory drugs and thalidomide merit definitive studies. Presently modern anticytokine treatments lack proof of broad effectiveness. Some NF-kappaB inhibitors hold early promise. Melatonin requires placebo-controlled trials before recommendations on clinical use. Oxidative stress probably contributes to muscle wasting. L-Carnitine and other antioxidants appear promising. Anticancer treatments designed as anticachexia interventions remain scarce.
SUMMARY
A number of promising new agents are in development but are not yet regarded as standard of care. This void calls for well-designed, proof-of-concept studies followed by placebo-controlled, randomized trials.
Topics: Appetite; Appetite Stimulants; Cachexia; Humans
PubMed: 18685381
DOI: 10.1097/SPC.0b013e3282f3474c -
Journal of Ethnopharmacology Oct 2019.Colorectal cancer (CRC) is now one the fourth cause of mortality and morbidity due to cancer throughout the globe. Cachexia is more prevalent in patients with this...
.Colorectal cancer (CRC) is now one the fourth cause of mortality and morbidity due to cancer throughout the globe. Cachexia is more prevalent in patients with this cancer and has a negative effect on response to chemotherapy and radiotherapy. Inflammatory cytokines such as TNF-α, IL-1β, and IL-6 could play a key role in cachexia. Moreover strong chemotherapy medications such as doxorubicin have complications such as toxicity and cachexia. Citrus unshiu Peel have been used as traditional herbal drugs for the treatment of cancer in traditional oriental medicine (TOM). Since its main components have anti-inflammatory effects, we evaluated the anti-cachexia activity in order to support the traditional usage of Citrus unshiu peel. Aim of the study; We aimed to assess the preventive or therapeutic effect of Citrus unshiu Peel Extract (CUPE) on cachexia by reducing of inflammatory cytokines in mice bearing C26 tumor. Also the contribution role of CUPE has evaluated on improvement of chemotherapy through reducing of inflammatory cytokines. Materials and Methods; The CUPE was prepared by Soxhlet extractor and quantitative and qualitative analysis of aqua extract was performed by high performance liquid chromatography (HPLC). C26 tumor bearing BALB/c male mice were immunized with different formulation of oral Prophylactic-therapeutic CUPE and/or intraperitoneal doxorubicin and then were monitored for weight gain, food intake and tumor size throughout the study. On the 32nd day after tumor injection, inflammatory cytokines levels, IL6, TNF-α and IL-1β were evaluated by Enzyme-linked Immunosorbent Assay (ELISA) and Malondialdehyde- Thiobarbituric acid (MDA) levels were measured by standard method. Results; Oral administration of CUPE in both prophylactic and therapeutic formulation to C26 adenocarcinoma bearing mice reduced the weight loss, tumor volume, and serum MDA levels compared with untreated tumor-bearing mice and Doxorubicin (Dox) groups. Also, the combination therapy of (CUPE + Dox) leads to reducing the levels of serum IL-6, TNF-α, IL-1β and tumor volume compared with untreated tumor-bearing mice and Dox groups. Serum MDA levels were considerably reduced by combination therapy of (CUPE + Dox) compared with Dox groups. Conclusions; These findings confirm the safety and efficacy of CUPE on C26 adenocarcinoma bearing mice as pure and adjuvant therapy, the results of which might be used in further human studies as a valuable natural anticancer agent alone or in combination with chemotherapy. Also the results showed that simultaneous application of CUPE and Dox leads to significant reduction of cachexia from the Dox chemotherapy.
Topics: Adenocarcinoma; Animals; Antibiotics, Antineoplastic; Cachexia; Cell Line; Citrus; Colonic Neoplasms; Cytokines; Doxorubicin; Male; Mice, Inbred BALB C; Plant Extracts; Tumor Burden
PubMed: 31054317
DOI: 10.1016/j.jep.2019.111929 -
Epigallocatechin-3-gallate effectively attenuates skeletal muscle atrophy caused by cancer cachexia.Cancer Letters Jun 2011Cachexia, also known as wasting syndrome notably with skeletal muscle atrophy, costs nearly one-third of all cancer deaths in man. (-)-Epigallocatechin-3-gallate (EGCG),...
Cachexia, also known as wasting syndrome notably with skeletal muscle atrophy, costs nearly one-third of all cancer deaths in man. (-)-Epigallocatechin-3-gallate (EGCG), the principal polyphenolic component in green tea, is a potent preventive against cachexia as well as cancers. However, how EGCG counteracts cachexia-provoked muscle wasting is unclear. EGCG was demonstrated to be able to retard tumor progression as well as to prevent body weight from loss, because EGCG attenuates skeletal muscle leukocytic infiltration and down-regulates tumor-induced NF-κB and E3-ligases in muscle. In mice, the dosages optimized against cachexia were determined to be 0.2 mg/mouse/day for prevention and to be 0.6 mg/mouse/day for treatment. Anti-cachexia effects were assessed using the LLC tumor model. Mice with the same body weight were divided into groups, including control, tumor bearing, and tumor-bearing but receiving water or EGCG in both prevention and treatment experiments. RT-PCR was used to assess mRNA expressions of NF-κB, MuRF 1, and MAFbx. The intracellular NF-κB, MuRF 1 and MAFbx were determined and quantified by immunofluorescence and Western blotting, respectively. Our results conclude EGCG regulates the expressions of NF-κB as well as downstream mediators, MuRF 1 and MAFbx, so EGCG may be an appropriate agent to be included in ensemble therapeutics of the tumor-induced muscle atrophy.
Topics: Animals; Anticarcinogenic Agents; Blotting, Western; Cachexia; Carcinoma, Lewis Lung; Catechin; Fluorescent Antibody Technique; Male; Mice; Mice, Inbred C57BL; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; NF-kappa B; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction; SKP Cullin F-Box Protein Ligases; Signal Transduction; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 21397390
DOI: 10.1016/j.canlet.2011.02.023 -
Journal of Ethnopharmacology Mar 2021Astragalus membranaceus (Fisch.) and Bunge and Paeonia japonica (Makino)Miyabe & H.Takeda have been traditionally used to improve the poor quality of life such as... (Comparative Study)
Comparative Study
ETHNOPHARMACOLOGICAL RELEVANCE
Astragalus membranaceus (Fisch.) and Bunge and Paeonia japonica (Makino)Miyabe & H.Takeda have been traditionally used to improve the poor quality of life such as weakness, lack of appetite, fatigue, and malaise which is considered with cachexia condition.
AIM OF THE STUDY
We investigated anti-cachectic effects of a herbal formula composed of Astragalus membranaceus and Paeonia japonica (APX) and the molecular mechanisms of APX in C26 cancer-induced cachexia mice and TNF-a-treated C2C12 myotubes. Additionally synergistic anti-cachectic effects of APX were compared to those of individual herbal extracts and megestrol acetate.
METHODS AND MATERIALS
The forty-two BALB/c mice were randomly divided into 6 groups: normal (nontreatment), control (C26 injection), AM (C26 injection with Astragalus membranaceus), PJ (C26 injection with Paeonia japonica), APX (C26 injection with combination of Astragalus membranaceus and Paeonia japonica and MA (C26 injection with megestrol acetate). All mice were orally administered DW (normal and control groups) or 100 mg/kg AM, PJ, APX or MA for 10 days. In the animal model, several tissues were weighed, and muscle tissue and blood were used to measure pro-inflammatory cytokines. C2C12 myotubes were exposed to 100 ng/mL TNF- α with or without 10 μg/mL of AM, PJ, APX or MA for 48 h. The cells were used to immunofluorescence staining and western blot analyses.
RESULTS
C26 injection induced notable body and muscle weight loss while APX administration significantly attenuated these alterations and the decrease of muscle weights and strength. APX also significantly attenuated the abnormal elevations in the concentration of three muscle atrophy-inducible cytokines; serum and muscle TNF-α,muscle TWEAK and IL-6 in C26 tumor-bearing mice. In the TNF-α-treated C2C12 myotube model, TNF-α treatment notably decreased MyH but activated atrophic proteins (MuRF and Fbx32) along with p38 and NFκB while these molecular alterations were significantly ameliorated by APX treatment. These pharmacological actions of APX were supported by the results of immunofluorescence staining to MyH expression and the translocation of NFκB into the nucleus in C2C12 myotubes.
CONCLUSIONS
Our data indicate the potential of an herbal formula, APX as an anti-cachexia agent; the effect of APX was superior to that of megestrol acetate overall especially for muscle atrophy. The underlying mechanisms of this herbal formula may involve the modulation of muscle atrophy-promoting molecules including p38, NFκB, TNF-α and TWEAK.
Topics: Animals; Astragalus propinquus; Cachexia; Cell Line, Tumor; Colonic Neoplasms; Cytokine TWEAK; Cytokines; Inflammation Mediators; Male; Mice; Mice, Inbred BALB C; Muscle, Skeletal; Muscular Atrophy; NF-kappa B; Paeonia; Plant Extracts; Signal Transduction; p38 Mitogen-Activated Protein Kinases
PubMed: 33068652
DOI: 10.1016/j.jep.2020.113470