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American Society of Clinical Oncology... 2015Many important advances have occurred in the field of cancer cachexia over the past decade, including progress in understanding the mechanisms of the cancer... (Review)
Review
Many important advances have occurred in the field of cancer cachexia over the past decade, including progress in understanding the mechanisms of the cancer anorexia-cachexia syndrome (CACS) and the development of promising pharmacologic and supportive care interventions. However, no approved agents for cancer cachexia currently exist, emphasizing the unmet need for an effective pharmacologic therapy. This article reviews the key elements of CACS assessment in daily practice, the contribution of nutritional impact symptoms (NIS), the evidence for current pharmacologic options, and promising anticachexia agents in perclinical and clinical trials. It also proposes a model for multimodality therapy and highlights issues pertinent to CACS in patients with pancreatic, gastric, and esophageal cancer.
Topics: Anorexia; Cachexia; Humans; Neoplasms; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 25993178
DOI: 10.14694/EdBook_AM.2015.35.e229 -
Journal of Nutrigenetics and... 2013Plant phenolics can inhibit, retard or reverse carcinogenesis, and may thus help prevent or treat cancer. Oil palm phenolics (OPP) previously showed anti-tumour...
BACKGROUND/AIM
Plant phenolics can inhibit, retard or reverse carcinogenesis, and may thus help prevent or treat cancer. Oil palm phenolics (OPP) previously showed anti-tumour activities in vivo via a cytostatic mechanism at 1,500 ppm gallic acid equivalent. Here, we report other possible molecular mechanisms by which this extract attenuates cancer, especially those concerning the immune response.
METHODS
We subcutaneously injected J558 myeloma cells in BALB/c mice and supplemented OPP orally at 1,500 ppm gallic acid equivalent. We observed the physiology parameters of these animals and harvested their spleens and livers after 18 h, 1 week and 4 weeks for microarray gene expression analysis using Illumina MouseRef-8 BeadChips.
RESULTS
Time course microarray analysis on spleens after injecting J558 myeloma cells in mice revealed that the immune response of tumour-bearing mice supplemented with OPP was lower compared to controls, thus suggesting delayed inflammation in response to OPP. In livers, cholesterol biosynthesis genes were upregulated while inflammatory genes were downregulated through time, further suggesting attenuation of systemic inflammation and cachexia. These effects correlated with the delayed in vivo development of syngeneic tumours in mice given OPP.
CONCLUSIONS
This study suggests the possible utilisation of OPP as an anti-tumour and anti-cachexia agent.
Topics: Animals; Cachexia; Dietary Supplements; Gallic Acid; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Inflammation; Liver; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Oligonucleotide Array Sequence Analysis; Palm Oil; Phenol; Plant Oils; Spleen; Tissue Distribution
PubMed: 24642698
DOI: 10.1159/000357948 -
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 -
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 -
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 -
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 -
Nutrition in Clinical Practice :... Apr 2006Cachexia involves progressive loss of adipose tissue and skeletal muscle mass and is common in a number of end-stage diseases. Cachexia causes weakness and immobility,... (Review)
Review
Cachexia involves progressive loss of adipose tissue and skeletal muscle mass and is common in a number of end-stage diseases. Cachexia causes weakness and immobility, reduces the quality of life of the patient, and eventually results in death. We reviewed the medical literature concentrating upon agents that have undergone clinical evaluation for the treatment of patients with cachexia. These agents are discussed, together with their mechanisms of action. Megestrol acetate, corticosteroids, eicosapentaenoic acid, and thalidomide have shown some success in the treatment of cachexia. beta-hydroxy-beta-methylbutyrate, cyclooxygenase inhibitors, adenosine 5'-triphosphate, and growth hormone are undergoing clinical evaluation. Appetite stimulants such as cannabinoids and antiserotonic agents have been shown to be ineffective in preventing progressive weight loss in cachexia. Much of the success in the treatment of cachexia has come from agents capable of blocking protein degradation through the ubiquitin-proteasome proteolytic pathway. Muscle mass can be increased when such agents are combined with agents that stimulate protein synthesis. In order to develop new agents, more fundamental research is required on the cellular mechanisms governing protein synthesis and degradation in skeletal muscle in cachexia.
Topics: Adipose Tissue; Adrenal Cortex Hormones; Cachexia; Eicosapentaenoic Acid; Energy Metabolism; Humans; Muscle, Skeletal; Progestins; Protein Biosynthesis; Thalidomide
PubMed: 16556927
DOI: 10.1177/0115426506021002168 -
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 -
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 -
Mini Reviews in Medicinal Chemistry Dec 2002The full-scale commercial appearance of antibiotics in the 1950's caused a shift of the nature of our lethal diseases from infectious/acute to non-infectious/chronic. In... (Review)
Review
The full-scale commercial appearance of antibiotics in the 1950's caused a shift of the nature of our lethal diseases from infectious/acute to non-infectious/chronic. In this situation, biological response modifiers (BRM's), which are not based on selective toxicity, are expected to be useful. There exist several types of BRM's, including retinoids which act directly on cells at the gene expression level, and thalidomide (and related molecules) which modulate internal circumstances of our body. We have been engaged in medicinal chemical/structural development studies based on these bio-active compounds. Retinoids include all-trans-retinoic acid (ATRA), a major active form of vitamin A (retinol), and its bio-isosters, which elicit their biological effects by binding to their nuclear receptors, RAR's. ATRA has been used in differentiation therapy [typically for the treatment of acute promyelocytic leukemia (APL)] and the treatment of dermatological diseases. Our structural development studies of retinoids, including computer-assisted molecular design has yielded class/subtype-selective agonists, synergists and antagonists of RAR's and their partner nuclear receptors, RXR's. Thalidomide elicits a wide range of pharmacological effects, including anti-cachexia, anti-angiogenic and anti-metastatic activities. We have found that thalidomide is a multi-target drug. Hypothetical target events/molecules of thalidomide include TNF-alpha production, nuclear androgen receptor, 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, anti-angiogenic agents, and anti-tumor promoting agents.
Topics: Adjuvants, Immunologic; Angiogenesis Inhibitors; Antineoplastic Agents; Drug Design; Humans; Retinoids; Structure-Activity Relationship; Thalidomide
PubMed: 12370039
DOI: 10.2174/1389557023405576