Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Understanding Cachexia: a major complication of cancer
Document related concepts
no text concepts found
Transcript
Understanding Cachexia: a major complication of cancer Pattarana Sae-Chew, Ph.D. What is Cachexia? Cachexia (Greek: Kachexi’a; Kako+e’xis) or Muscle wasting Severe, chronic, unintentional, and progressive weight loss Loss of adipose tissue and lean body mass Visceral protein preserved chronic diseases Congestive Heart Failure Acquired Immunodeficiency Syndrome Chronic Malaria Rheumatoid Arthritis Chronic Obstructive Pulmonary Disease Cancer Metabolic alterations in Cachexia Anorexia: Loss of Appetite Early satiety Anemia Lypolysis Resting energy expenditure Activation of acute phase response Insulin resistance Clinical Definition In 2006, Fearon KC., et al. proposed definition for cancer cachexia Body weight loss ≥10% Nutrient intake ≤1,500 kcal/day Level of C-reactive protein ≥10mg/L Advantages Strong clinically and pathophysiologically supported Prognostically validated Based on objective criteria Clinical Definition In 2006, Fearon KC., et al. proposed definition for cancer cachexia Body weight loss ≥10% Nutrient intake ≤1,500 kcal/day Level of C-reactive protein ≥10mg/L Limitations Does not classify cachexia Difficulty in accessing calorie intake for out-pateint Cachexia vs. Starvation Starvation: depletes fat stores from adipose tissue while conserving protein from skeletal muscle Nutrition supplements for cachexia treatment Promote weight gain due to the replenishment of fat Ineffective to restore skeletal muscle protein content Public Health Significance Cancer-cachexia Debilitating & life threatening 5 millions U.S. (in Thailand???) Poor prognosis, quality of life Increase patient susceptibility No effective treatment High public health cost Personal & family suffering Cancer-cachexia incidence Laviano A., et al. Nat Clin Pract Oncol. 2005 Mar;2(3) Consequences of wasting Muscle fiber size and protein content Force and power output Fatigue Asthenia Prognosis, response to therapy, Quality of life Immobility Cardiac or respiratory failure: 20% mortality Muscle fiber size in cachexia Non-tumor-bearing c26-tumor-bearing Consequences of wasting Muscle fiber size and protein content Force and power output Fatigue Asthenia Prognosis, response to therapy, Quality of life Immobility Cardiac or respiratory failure: 20% mortality Underlying mechanism Exact mechanism ???? proinflammatory cytokines TNF-a IL-1 IL-6 IFN-g Cytokines as cachexia mediator Diseased group: A = healthy control B = patients w organ-confined CaP C = patients w advanced CaP Ca = noncachectic advanced CaP Cb = cachectic advanced CaP 13 Pfitzenmaier J et al. Cancer. (2003) Cytokine vs. BMI Kuroda K., et al. Clin Cancer Res. (2005) Cytokines and Cachexia 240% Stephens NA, Curr Opin Support Palliat Care. 2008 Dec;2(4):267-74. 15 Proteolysis Ubiquitin-Proteasome System (UPS) Muscle-specific E3: MuRF1, MAF/bx Cytokines-induced muscle protein degradation TNF-a TRADD RIP Ub TRAF2 P Ub Ub Ub P Ub P IkB-a 26S proteasome Ub K48 Ub Ub Ub P P g b a Ub Cytoplasm Ub Ub Ub K63 P IKK complex P P IkB-a IkB-a p50 p65 Ub p50 p65 P p50 p65 NF-kB target genes 17 Activation of NF-kB Nuclear factor kB (NF-kB) Signaling pathway TNF-a activation of NF-kB pathway in muscle wasting conditions during disease states Required for muscle degradation Inhibits skeletal myogenesis in vitro Tada K., et al. J Biol Chem. 2001 Sep 28;276(39) 18 TNF-a promotes myofibrillar proteins loss Guttridge DC., et al. Science. 2000 19 Cytokines-induced muscle protein degradation Cytokines NF-kB YY1 Ubiquitin-Proteasome 20S, MuRF1, MAF/bx MyoD, myogenin MyHC = Activation = Inhibition Cytokines and Cachexia 60% Stephens NA, Curr Opin Support Palliat Care. 2008 Dec;2(4):267-74. 21 Depression of protein synthesis 22 Depression of protein synthesis PIF, Ang II PKR e-IF2a p-PKR p-e-IF2a Inhibition of translation initiation Depression of protein synthesis 24 Depression of protein synthesis Depression of protein synthesis 26 Protein translation factors in cachexia Treatment for Cachexia Most effective “Treat diseases origin of cachexia” AIDS Cancer Congestive Heart Failure COPD Pre-clinical study Effect of Branched-Chain Amino Acids on Muscle Atrophy in Cancer Cachexia, Helen L. Eley, Steven T. Russell, and Michael J. Tisdale Biochem. J. Oct. 2007 Val Leu Ile PBS Pre-clinical study Amelioration of Cancer-Induced Cachexia by Inhibition of NF-kB Signaling Pathway, Pattarana Sae-Chew and Paula R. Clemens tumor weight (mg) 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Tumor weight 0 2 4 6 8 10 12 14 16 18 20 NTB Days 10 TBC i.m. 5 % change 0 -5 0 2 4 6 8 10 12 14 -10 -15 -20 -25 -30 Percent weight change 16 18 20 i.v. Treatment for Cachexia Table 1. Drugs candidates for the treatment of cancer cachexia. Drug Type of study Action Effects Increase in food intake, energy expenditure decrease and weight gain Melanocortin receptor antagonists Experimental studies Blockade of the melanocortin receptor Ghrelin Human clinical trial Stimulation of appetite Energy intake increase and improvement in the perceived pleasantness of meal Pentoxifyllin Human clinical trial Downregulation of the production of TNF-α No significant weight gain Thalidomide Human clinical trials Improvement of subjective Downregulation of the production of TNF-α and other symptoms of cachexia, weight gain pro-inflammatory cytokines and reduction in loss of lean body mass Melatonin Human clinical trials Downregulation of the release of cytokines Anti-TNF drugs Experimental studies Inhibition of the TNF action β-hydroxy-β-methylbutyrate Human clinical trial Inhibition of proteasome activity Inhibition of wasting, weight and lean body mass gain Lean body mass gain Bortezomib Experimental studies Inhibition of proteasome activity Reduction of muscle proteolysis Calpain inhibitors Experimental studies Inhibition of calpain activity Inhibition of protein breakdown Antimyostatin antibodies Experimental studies Inhibition of myostatin action Improvement of muscle function and reduction of muscle degeneration Inhibitors of NF-κB Experimental studies Inhibition of translocation of NF-κB into the nucleus Attenuate protein degradation Inhibitors of protine kinase R Experimental studies Downregulation of the expression of the ubiquitinproteasome pathway Nandrolone decanoate/Oxandrolone Human clinical trials Stimulation of protein anabolism in muscle 31 Weight stabilisation or gain Attenuate depression of protein synthesis and increased protein degradation Weight gain and improvement of lean body mass Treatment for Cachexia Table 2. Ongoing clinical trials in cancer cachexia. Drug Phase of study Type of patients Primary outcomes RC-1291 (ghrelin-like activity NCT00378131 drug) II Incurable histologically diagnosed cancer Body weight; Lean body mass; functional performance Thalidomide ISRCTN51456701 II/III Upper gastrointestinal cancer Weight change Thalidomide NCT00379353 NA Advanced cancer Effect on anorexia, fatigue, nausea and weight loss Thalidomide N0077075338 III Inoperable esophageal cancer Metabolic rate, weight change and quality of life Etanercept NCT00046904 III Unspecified adult advanced solid tumour Weight gain and weight change Etanercept NCT00127387 II/III Lung, Prostate, Bone cancer and metastasis during radiotherapy Safety; quality of life Infliximab NCT00060502 II/III Pancreatic cancer Change in lean body mass Infliximab NCT00040885 III NSCLC in treatment with docetaxel Weight and lean body mass change 32 Study number Cancer in Thailand Cancer in Thailand Cancer in Thailand Cachexia in Thailand Where are we ??????? Q&A Comments Thank you Skeletal Muscle Differentiation Mesodermal Myoblast Multinucleated progenitor Pax3 Pax7 myotube MyoD Myf5 myotube Myogenin MRF4 MHC MCK 38 Mature Introduction During skeletal differentiation Myogenic bHLH transcription factor family MyoD, Myf5, myogenin, MRF-4, and the MEF-2 family of transcription factors Is activated and followed by terminal cell cycle arrest Regulate the late phase of myogenesis by inducing the expression of myofibrillar protein such as MHC Ultimately leads to the fusion of myoblasts into mutinucleated myotubes 39 Introduction Stephens NA., et al. Curr Opin Support Palliat Care 2008, 2:267–274 40
