Advertisement

Melanocortin system in cancer-related cachexia

  • Julie Bienertová-VaškůEmail author
  • Petr Bienert
  • Dalibor Valík
  • Anna Vašků
Research Article
  • 60 Downloads

Abstract

The melanocortin system plays a pivotal role in the regulation of appetite and energy balance. It was recognized to play an important role in the development of cancer-related cachexia, a debilitating condition characterized by progressive body wasting associated with anorexia, increased resting energy expediture and loss of fat as well as lean body mass that cannot be simply prevented or treated by adequate nutritional support.

The recent advances in understanding of mechanisms underlying cancer-related cachexia led to consequent recognition of the melanocortin system as an important potential therapeutic target. Several molecules have been made available for animal experiments, including those with oral bioavailability, that act at various checkpoints of the melanocortin system and that might confer singificant benefits for the patients suffering from cancer-related cachexia. The application of melanocortin 4 receptor antagonists/agouti-related peptide agonists has been however restricted to animal models and more pharmacological data will be necessary to progress to clinical trials on humans. Still, pharmacological targeting of the melanocortin system seem to represent an elegant and promising way of treatment of cancer-related cachexia.

Keywords

Melanocortins Agouti-related peptide Cancer Cachexia 

References

  1. [1]
    Argilés J.M., Moore-Carrasco R., Busquets S., López-Soriano F.J. Catabolic mediators as targets for cancer cachexia. Drug Discov Today., 2003, 18, 838–844CrossRefGoogle Scholar
  2. [2]
    Tisdale M.J. Cachexia in cancer patients. Nat Rev Cancer., 2002, 11, 862–871CrossRefGoogle Scholar
  3. [3]
    DeWys W.D., Weight loss and nutritional abnormalities in cancer patients: incidence, severity and significance. In: Clinics in Oncology, Calman K.C., Fearon K.C.H. (Eds.) London: Saunders, vol. 5, no. 2, p. 251–261., 1986Google Scholar
  4. [4]
    Laviano A, Meguid MM, Inui A, Muscaritoli M, Rossi-Fanelli F. Therapy insight: Cancer anorexia-cachexia syndrome—when all you can eat is yourself. Nat Clin Pract Oncol., 2005, 3, 158–165CrossRefGoogle Scholar
  5. [5]
    Evans W.J., Morley J.E., Argiles J., Bales C., Baracos V., et al. Cachexia: A new definition. Clin Nutr 27., 2008, 793–799PubMedCrossRefGoogle Scholar
  6. [6]
    Tisdale M.J. Are tumoral factors responsible for host tissue wasting in cancer cachexia? Future Oncol., 2010, 4, 503–513CrossRefGoogle Scholar
  7. [7]
    Fearon K.C.H., Voss A.S., Hustend D.S. Definition of cancer cachexia: effect of weight loss, reduced food intake and systemic inflammation on functional status and prognosis. Am J Clin Nutr., 2006, 83, 1345–1350PubMedGoogle Scholar
  8. [8]
    DeWys W.D. Weight loss and nutritional abnormalities in cancer patients: incidence, severity and significance. In: Clinics in Oncology, edited by Calman KC and Fearon KCH. London: Saunders, 1986, vol. 5, no. 2, p. 251–261Google Scholar
  9. [9]
    Bing C., Brown M., King P., Collins P., Tisdale M.J., Williams G. Increased gene expression of brown fat uncoupling protein (UCP)1 and skeletal muscle UCP2 and UCP3 in MAC16-induced cancer cachexia. Cancer Res. 2000, 9, 2405–2410Google Scholar
  10. [10]
    Kulstad R., Schoeller D.A. The energetics of wasting diseases. Curr Opin Clin Nutr Metab Care., 2007, 4, 488–493Google Scholar
  11. [11]
    Bennani-Baiti N., Davis M.P.. Cytokines and cancer anorexia cachexia syndrome. Am J Hosp Palliat Care. 2008, 5, 407–411CrossRefGoogle Scholar
  12. [12]
    Yavuzsen T., Davis M.P., Walsh D., LeGrand S., Lagman R. Systematic review of the treatment of cancer-associated anorexia and weight loss. J Clin Oncol., 2005, 23, 8500–8511PubMedCrossRefGoogle Scholar
  13. [13]
    DeBoer M.D. Update on melanocortin interventions for cachexia: progress toward clinical application. Nutrition., 2010, 2,146–151CrossRefGoogle Scholar
  14. [14]
    Scarlett J.M., Marks D.L. The use of melanocortin antagonists in cachexia of chronic disease. Expert Opin Investig Drugs., 2005, 14,1233–1239PubMedCrossRefGoogle Scholar
  15. [15]
    Marks D.L., Ling N., Cone R.D. Role of the central melanocortin system in cachexia. Cancer Res 2001;61:1432–1438PubMedGoogle Scholar
  16. [16]
    Wisse B.E., Frayo R.S., Schwartz M.W., Cummings D.E. Reversal of cancer anorexia by blockade of central melanocortin receptors in rats. Endocrinology., 2001,142, 3292–3301PubMedCrossRefGoogle Scholar
  17. [17]
    Tung Y.C., Yeo G.S. Central melanocortin signaling regulates cholesterol. Nat Neurosci., 2010, 7, 779–780CrossRefGoogle Scholar
  18. [18]
    Stewart P.M., Boulton A., Kumar S., Clark P.M., Shackleton C.H.. Cortisol metabolism in human obesity: impaired cortisone—>cortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab., 1999, 3, 1022–1027CrossRefGoogle Scholar
  19. [19]
    Cone R.D. Anatomy and regulation of the central melanocortin system. Nat Neurosci., 2005, 5, 571–578CrossRefGoogle Scholar
  20. [20]
    Whitaker K.W., Reyes T.M. Central blockade of melanocortin receptors attenuates the metabolic and locomotor responses to peripheral interleukin-1beta administration. Neuropharmacology., 2008, 54, 509–520PubMedCrossRefGoogle Scholar
  21. [21]
    Ellacott K.L., Halatchev I.G., Cone R.D. Interactions between gut peptides and the central melanocortin system in the regulation of energy homeostasis. Peptides., 2006, 2, 340–349CrossRefGoogle Scholar
  22. [22]
    Marks D.L., Cone R.D. The role of the melanocortin-3 receptor in cachexia. Ann N Y Acad Sci., 2003, 994, 258–266PubMedCrossRefGoogle Scholar
  23. [23]
    Cone R.D. Studies on the physiological functions of the melanocortin system. Endocr Rev., 2006, 7, 736–749Google Scholar
  24. [24]
    Butler A.A., Marks D.L., Fan W., Kuhn C.M., Bartolome M., Cone R.D. Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat Neurosci., 2001, 6, 605–611CrossRefGoogle Scholar
  25. [25]
    Tung Y.C., Piper S.J., Yeung D., O’Rahilly S., Coll A.P. A comparative study of the central effects of specific proopiomelancortin (POMC)-derived mela nocortin peptides on food intake and body weight in pomc null mice. Endocrinology., 2006, 12, 5940–5947CrossRefGoogle Scholar
  26. [26]
    Coll A.P. Effects of pro-opiomelanocortin (POMC) on food intake and body weight: mechanisms and therapeutic potential? Clin Sci (Lond)., 2007, 4, 171–182Google Scholar
  27. [27]
    Jackson P.J., Yu B., Hunrichs B., Thompson D.A., Chai B., Gantz I., Millhauser G.L. Chimeras of the agouti-related protein: insights into agonist and antagonist selectivity of melanocortin receptors. Peptides., 2005, 10, 1978–1987CrossRefGoogle Scholar
  28. [28]
    Fan W., Boston B.A., Kesterson R.A., Hruby V.J., Cone R.D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature, 1997, 385,165–168PubMedCrossRefGoogle Scholar
  29. [29]
    Ollmann M.M., Wilson B.D., Yang Y.K., Kerns J.A., Chen Y., Gantz I., et al. Antagonism of central melanocortin receptors in vitro and in vivo by agoutirelated protein. Science,1997, 278,135–138PubMedCrossRefGoogle Scholar
  30. [30]
    Farooqi I.S., Keogh J.M., Yeo G.S., Lank E.J., Cheetham T., O’Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med., 2003, 348, 1085–1095PubMedCrossRefGoogle Scholar
  31. [31]
    Olszewski P.K., Wickwire K., Wirth M.M., Levine A.S., Giraudo S.Q. Agouti-related protein: appetite or reward? Ann N Y Acad Sci., 2003, 994,187–191PubMedCrossRefGoogle Scholar
  32. [32]
    Hagan M.M., Rushing P.A., Benoit S.C., Woods S.C., Seeley R.J. Opioid receptor involvement in the effect of AgRP — (83–132) on food intake and food selection. Am J Physiol Regul Integr Comp Physiol., 2001, 3,:R814–R821Google Scholar
  33. [33]
    Butler A.A., Cone R.D. Knockout studies defining different roles for melanocortin receptors in energy homeostasis. Ann N Y Acad Sci., 2003, 994, 240–245.PubMedCrossRefGoogle Scholar
  34. [34]
    Ste Marie L., Miura G.I., Marsh D.J., Yagaloff K., Palmiter R.D. A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc Natl Acad Sci U S A., 2000,97,12339–12344PubMedCrossRefGoogle Scholar
  35. [35]
    Stütz A.M., Morrison C.D., Argyropoulos G. The agouti-related protein and its role in energy homeostasis. Peptides., 2005, 10,1771–1781CrossRefGoogle Scholar
  36. [36]
    Ilnytska O., Argyropoulos G. The role of the Agouti-Related Protein in energy balance regulation. Cell Mol Life Sci., 2008, 17, 2721–2731CrossRefGoogle Scholar
  37. [37]
    Qian S., Chen H., Weingarth D., Trumbauer ME., Novi D.E., Guan X. et al. Neither Agouti-Related Protein nor Neuropeptide Y Is Critically Required for the Regulation of Energy Homeostasis in Mice. Mol. Cell. Biol., 2002, 22, 5027–5035PubMedCrossRefGoogle Scholar
  38. [38]
    Wortley K.E., Anderson K.D., Yasenchak J., Murphy A., Valenzuela D., Diano S. et al. Agoutirelated protein-deficient mice display an age-related lean phenotype. Cell. Metab., 2005, 2, 421–427PubMedCrossRefGoogle Scholar
  39. [39]
    Vaughan C.H., Moore M.C., Haskell-Luevano C., Rowland N.E. Meal patterns and foraging in melanocortin receptor knockout mice. Physiol Behav., 2005, 1, 129–133CrossRefGoogle Scholar
  40. [40]
    Koegler F.H., Schaffhauser R.O., Mynatt R.L., York D.A., Bray G.A. Macronutrient diet intake of the lethal yellow agouti (Ay/a) mouse. Physiol Behav., 1999, 5, 809–812CrossRefGoogle Scholar
  41. [41]
    Cheung W.W., Kuo H.J., Markison S., Chen C., Foster A.C., Marks D.L. et al. Peripheral administration of the melanocortin-4 receptor antagonist NBI-12i ameliorates uremia-associated cachexia in mice. J Am Soc Nephrol., 2007, 9, 2517–2524CrossRefGoogle Scholar
  42. [42]
    Bowe D.D., Scarlett J.M., Basra A.K., Steiner R.A., Marks D.L. Blockade of central melanocortin signaling promotes accumulation of lean body mass in rodent models of chronic heart failure. J Investig Med., 2007, 55:S77Google Scholar
  43. [43]
    Basra A.K., Scarlett J.M., Bowe D.D., Steiner R.A., Marks D.L. Central melanocortin blockade attenuates cardiac cachexia in a rat model of chronic heart failure. J Investig Med., 2008, 56, 229–230Google Scholar
  44. [44]
    Nicholson J.R., Kohler G., Schaerer F., Senn C., Weyermann P., Hofbauer K.G. Peripheral administration of a melanocortin 4-receptor inverse agonist prevents loss of lean body mass in tumor-bearing mice. J Pharmacol Exp Ther., 2006, 2, 771–777CrossRefGoogle Scholar
  45. [45]
    Weyermann P., Dallmann R., Magyar J., Anklin C., Hufschmid M., Dubach-Powell J. et al. Orally available selective melanocortin-4 receptor antagonists stimulate food intake and reduce cancer-induced cachexia in mice. PLoS One., 2009; 4(3), e4774PubMedCrossRefGoogle Scholar
  46. [46]
    Tung Y.C., Piper S.J., Yeung D., O’Rahilly S. and Coll A.P. A comparative study of the central effects of specific proopiomelancortin (POMC)-derived melanocortin peptides on food intake and body weight in pomc null mice. Endocrinology 2006, 147, 5940–5947PubMedCrossRefGoogle Scholar
  47. [47]
    Hoggard N., Rayner D.V., Johnston S.L., Speakman J.R. Peripherally administered [Nle4,D-Phe7]-alpha-melanocyte stimulating hormone increases resting metabolic rate, while peripheral agouti-related protein has no effect, in wild type C57BL/6 and ob/ob mice. J Mol Endocrinol 2004; 33, 693–703PubMedCrossRefGoogle Scholar
  48. [48]
    Markison S., Foster A.C., Chen C., Brookhart G.B., Hesse A., Hoare S.R. The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonist. Endocrinology., 2005, 146(6),2766–2773PubMedCrossRefGoogle Scholar
  49. [49]
    Santhera Pharmaceuticals (Switzerland) AG (2008) Preparation of imidazopyridines as melanocortin-4 receptor antagonists. WO 2008/116665 A1Google Scholar
  50. [50]
    Santhera Pharmaceuticals (Switzerland) AG (2009) Subsituted heteroarylpiperidine derivatives as melanocortin-4 receptor modulators. WO 2009/010299 A1Google Scholar
  51. [51]
    Joppa M.A., Ling N., Chen C., Gogas K.R., Foster A.C., Markison S. Central administration of peptide and small molecule MC4 receptor antagonists induce hyperphagia in mice and attenuate cytokine-induced anorexia. Peptides., 2005, 26(11), 2294–2301PubMedCrossRefGoogle Scholar
  52. [52]
    Chen C., Tucci F.C., Jiang W., Tran J.A., Fleck B.A., Hoare S.R. Pharmacological and pharmacokinetic characterization of 2-piperazine-alpha-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists. Bioorg Med Chem., 2008,16(10), 5606–5618PubMedCrossRefGoogle Scholar
  53. [53]
    Vos T.J., Caracoti A., Che J.L., Dai M., Farrer C.A., Forsyth N.E., et al. Identification of 2-[2-[2-(5-bromo-2 — methoxyphenyl)-ethyl]-3-fluorophenyl]-4,5-dihydro-1H-imidazole (ML00253764), a small molecule melanocortin 4 receptor antagonist that effectively reduces tumor-induced weight loss in a mouse model. J Med Chem., 2004,47(7),1602–164PubMedCrossRefGoogle Scholar
  54. [54]
    Cheung W.W., Kuo H.J., Markison S., Chen C., Foster A.C., Marks D.L. et al. Peripheral administration of the melanocortin-4 receptor antagonist NBI-12i ameliorates uremia-associated cachexia in mice. J Am Soc Nephrol., 2007, 18(9), 2517–2524PubMedCrossRefGoogle Scholar
  55. [55]
    Nijenhuis W.A., Oosterom J., Adan R.A.. AgRP(83–132) acts as an inverse agonist on the human-melanocortin-4 receptor. Mol Endocrinol., 2001, 15(1), 164–171PubMedCrossRefGoogle Scholar
  56. [56]
    Oosterom J., Garner K.M., den Dekker W.K., Nijenhuis W.A., Gispen W.H., Burbach J.P, et al. Common requirements for melanocortin-4 receptor selectivity of structurally unrelated melanocortin agonist and endogenous antagonist, Agouti protein. J Biol Chem., 2001, 276(2), 931–936PubMedCrossRefGoogle Scholar
  57. [57]
    Adan R.A., Tiesjema B., Hillebrand J.J., la Fleur S.E., Kas M.J., de Krom M. The MC4 receptor and control of appetite. Br J Pharmacol., 2006, 149(7), 815–827PubMedCrossRefGoogle Scholar
  58. [58]
    Joseph C.G., Bauzo R.M., Xiang Z., Shaw A.M., Millard W.J., Haskell-Luevano C. Elongation studies of the human agouti-related protein (AGRP) core decapeptide (Yc[CRFFNAFC]Y) results in antagonism at the mouse melanocortin-3 receptor. Peptides., 2003, 24(2), 263–270PubMedCrossRefGoogle Scholar
  59. [59]
    Fu L.Y., van den Pol A.N. Agouti-related peptide and MC3/4 receptor agonists both inhibit excitatory hypothalamic ventromedial nucleus neurons. J Neurosci., 2008, 28(21), 5433–5449PubMedCrossRefGoogle Scholar
  60. [60]
    Tisdale M.J. Clinical anticachexia treatments. Nutr Clin Pract., 2006, 21(2), 168–174PubMedCrossRefGoogle Scholar
  61. [61]
    Rigas J.R., Schuster M., Orlov S.V., Milovanovic B., Prabhash K., Smith J.T. and the ALD518 study group. Affect of ALD518, a humanized anti-IL-6 antibody, on lean body mass loss and symptoms in patients with advanced non-small cell lung cancer (NSCLC): Results of a phase II randomized, double-blind safety and efficacy trial. J Clin Oncol 28 (1534). http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=50646
  62. [62]
    Steiner M.S., Barnette K.G., Hancock M.L., Dodson S.T., Rodriguez D., Morton R.A.; GTx, Inc., Memphis, TN (June 2010). „Effect of GTx-024, a selective androgen receptor modulator (SARM), on stair climb performance and quality of life (QOL) in patients with cancer cachexia”. J Clin Oncol 28 (1534) http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=52947
  63. [63]
    Bhattacharyya G.S., Julka P.K., Bondarde S., Naik R., Ranade A., Bascomb N. et al. (June 2010). „Phase II study evaluating safety and efficacy of coadministering propranolol and etodolac for treating cancer cachexia”. J Clin Oncol 28 (1534). http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=49474
  64. [64]
    Zhou X., Wang J.L., Lu J., Song Y., Kwak K.S., Jiao Q. et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell., 2010, 142(4), 531–543.PubMedCrossRefGoogle Scholar
  65. [65]
    Trials for cachexia treatment. Available at: http://clinicaltrials.gov/ct2/results?term¼cachexia&pg¼4. Accessed September 1, 2010

Copyright information

© © Versita Warsaw and Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Julie Bienertová-Vašků
    • 1
    • 2
    Email author
  • Petr Bienert
    • 1
  • Dalibor Valík
    • 2
  • Anna Vašků
    • 1
  1. 1.Department of Pathological Physiology, Faculty of MedicineMasaryk UniversityBrnoCzech Republic
  2. 2.Department of Laboratory MedicineMasaryk Memorial Cancer InstituteBrnoCzech Republic

Personalised recommendations