Preferences help
enabled [disable] Abstract
Number of results
2011 | 6 | 5 | 550-557
Article title

Melanocortin system in cancer-related cachexia

Title variants
Languages of publication
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.
Physical description
1 - 10 - 2011
9 - 8 - 2011
  • Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5 A18, 625 00, Brno, Czech Republic
  • Department of Laboratory Medicine, Masaryk Memorial Cancer Institute, Brno, Czech Republic
  • Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5 A18, 625 00, Brno, Czech Republic
  • [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, 838–844[Crossref]
  • [2] Tisdale M.J. Cachexia in cancer patients. Nat Rev Cancer., 2002, 11, 862–871[Crossref]
  • [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., 1986
  • [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, 158–165[Crossref]
  • [5] Evans W.J., Morley J.E., Argiles J., Bales C., Baracos V., et al. Cachexia: A new definition. Clin Nutr 27., 2008, 793–799[Crossref]
  • [6] Tisdale M.J. Are tumoral factors responsible for host tissue wasting in cancer cachexia? Future Oncol., 2010, 4, 503–513[Crossref]
  • [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, 1345–1350
  • [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. 251–261
  • [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, 2405–2410
  • [10] Kulstad R., Schoeller D.A. The energetics of wasting diseases. Curr Opin Clin Nutr Metab Care., 2007, 4, 488–493 [PubMed][Crossref]
  • [11] Bennani-Baiti N., Davis M.P.. Cytokines and cancer anorexia cachexia syndrome. Am J Hosp Palliat Care. 2008, 5, 407–411[Crossref]
  • [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, 8500–8511[Crossref]
  • [13] DeBoer M.D. Update on melanocortin interventions for cachexia: progress toward clinical application. Nutrition., 2010, 2,146–151[Crossref]
  • [14] Scarlett J.M., Marks D.L. The use of melanocortin antagonists in cachexia of chronic disease. Expert Opin Investig Drugs., 2005, 14,1233–1239[Crossref]
  • [15] Marks D.L., Ling N., Cone R.D. Role of the central melanocortin system in cachexia. Cancer Res 2001;61:1432–1438
  • [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, 3292–3301[Crossref]
  • [17] Tung Y.C., Yeo G.S. Central melanocortin signaling regulates cholesterol. Nat Neurosci., 2010, 7, 779–780[Crossref]
  • [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, 1022–1027[Crossref]
  • [19] Cone R.D. Anatomy and regulation of the central melanocortin system. Nat Neurosci., 2005, 5, 571–578[Crossref]
  • [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, 509–520[Crossref]
  • [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, 340–349[Crossref]
  • [22] Marks D.L., Cone R.D. The role of the melanocortin-3 receptor in cachexia. Ann N Y Acad Sci., 2003, 994, 258–266[Crossref]
  • [23] Cone R.D. Studies on the physiological functions of the melanocortin system. Endocr Rev., 2006, 7, 736–749 [Crossref]
  • [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, 605–611[Crossref]
  • [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, 5940–5947[Crossref]
  • [26] Coll A.P. Effects of pro-opiomelanocortin (POMC) on food intake and body weight: mechanisms and therapeutic potential? Clin Sci (Lond)., 2007, 4, 171–182
  • [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, 1978–1987[Crossref]
  • [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, 385,165–168[Crossref]
  • [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, 278,135–138[Crossref]
  • [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, 1085–1095[Crossref]
  • [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, 994,187–191[Crossref]
  • [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–R821
  • [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.[Crossref]
  • [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., 2000,97,12339–12344[Crossref]
  • [35] Stütz A.M., Morrison C.D., Argyropoulos G. The agouti-related protein and its role in energy homeostasis. Peptides., 2005, 10,1771–1781[Crossref]
  • [36] Ilnytska O., Argyropoulos G. The role of the Agouti-Related Protein in energy balance regulation. Cell Mol Life Sci., 2008, 17, 2721–2731[Crossref]
  • [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, 5027–5035[Crossref]
  • [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, 421–427[Crossref]
  • [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, 129–133[Crossref]
  • [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, 809–812[Crossref]
  • [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, 2517–2524[Crossref]
  • [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:S77
  • [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, 229–230
  • [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, 771–777
  • [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), e4774[Crossref]
  • [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, 5940–5947[Crossref]
  • [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, 693–703
  • [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),2766–2773[Crossref]
  • [49] Santhera Pharmaceuticals (Switzerland) AG (2008) Preparation of imidazopyridines as melanocortin-4 receptor antagonists. WO 2008/116665 A1
  • [50] Santhera Pharmaceuticals (Switzerland) AG (2009) Subsituted heteroarylpiperidine derivatives as melanocortin-4 receptor modulators. WO 2009/010299 A1
  • [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), 2294–2301[Crossref]
  • [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), 5606–5618[Crossref]
  • [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),1602–164
  • [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), 2517–2524[Crossref]
  • [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), 164–171[Crossref]
  • [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), 931–936[Crossref]
  • [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), 815–827[Crossref]
  • [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), 263–270[Crossref]
  • [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), 5433–5449[Crossref]
  • [60] Tisdale M.J. Clinical anticachexia treatments. Nutr Clin Pract., 2006, 21(2), 168–174[Crossref]
  • [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).
  • [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)
  • [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).
  • [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.[Crossref]
  • [65] Trials for cachexia treatment. Available at:¼cachexia&pg¼4. Accessed September 1, 2010
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.