Ursodeoxycholic acid treatment in a rat model of cancer cachexia
Cancer cachexia is characterized by loss of both adipose and skeletal muscle tissue and by an increased production of proinflammatory cytokines. Ursodeoxycholic acid (UDCA), a bile acid used for centuries in the treatment of liver disease, is known to confer anti-inflammatory and anti-apoptotic effects as well as beneficial effects on mitochondrial integrity and cell signaling. We hypothesized that UDCA ameliorates the wasting process in the Yoshida hepatoma tumor model. In addition, we sought to establish if UDCA exerts beneficial effects on survival in this model.
Methods and results
Forty-seven male rats were inoculated intraperitoneally with 108 Yoshida hepatoma AH-130 cells and treated with placebo or one of two different doses of UDCA, 25 or 100 mg/kg daily. Body weight, body composition, and activity indicators were measured over the course of study up to day 16. UDCA treatment had no effect on tumor growth, loss of body weight, and loss of fat mass. Compared with placebo, low-dose UDCA improved tissue loss in the lung (p = 0.022) and tended to reduce tissue loss in brown adipocytes (p = 0.06), gastrocnemius muscle (p = 0.06), extensor digitorum longus muscle (p = 0.09), and soleus muscle (p = 0.07). Compared with placebo, high-dose UDCA tended to reduce the loss of lean body mass (p = 0.06), lung tissue (p = 0.1), white adipose tissue (p = 0.11), and gastrocnemius muscle (p = 0.11). The activity and food intake were not altered in tumor-bearing rats by either dose of UDCA. Both doses tended to decrease the mortality rate in tumor-bearing rats, (hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.17–1.04; p = 0.061 for low-dose UDCA; HR, 0.44; 95% CI, 0.18–1.05; p = 0.065 for high-dose UDCA).
UDCA treatment in the Yoshida hepatoma model showed a trend towards attenuation of tissue loss in animals with progressive weight loss in cancer cachexia. Tumor growth and activity indicators were not altered. Both doses of UDCA tended to reduce the mortality rates in tumor-bearing animals. Larger studies with longer follow-up are required to verify these findings.
Supplementary Material (0)
- von Haehling S, Morley JE, Anker SD. An overview of sarcopenia: facts and numbers on prevalence and clinical impact. J Cachexia Sarcopenia Muscle. 2010;1:129–33. CrossRef
- Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, Guttridge D, et al. Cachexia: a new definition. Clin Nutr. 2008;27:793–9. CrossRef
- von Haehling S. Cachexia as a major underestimated and unmet medical need: facts and numbers. J Cachexia Sarcopenia Muscle. 2010;1:1–5. CrossRef
- Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev. 2009;89:381–410. CrossRef
- Matthys P, Billiau A. Cytokines and cachexia. Nutrition. 1997;13:763–70. CrossRef
- Sharma R, Prichard D, Majer F, Byrne AM, Kelleher D, Long A, et al. Ursodeoxycholic acid amides as novel glucocorticoid receptor modulators. J Med Chem. 2011;54:122–30. CrossRef
- Cronin J, Williams L, McAdam E, Eltahir Z, Griffiths P, Baxter J, et al. The role of secondary bile acids in neoplastic development in the oesophagus. Biochem Soc Trans. 2010;38:337–42. CrossRef
- Heathcote EJ. Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines. Hepatology. 2000;31:1005–13. CrossRef
- Narisawa T, Fukaura Y, Terada K, Sekiguchi H. Prevention of N-methylnitrosourea-induced colon tumorigenesis by ursodeoxycholic acid in F344 rats. Jpn J Cancer Res. 1998;89:1009–13. CrossRef
- Earnest DL, Holubec H, Wali RK, Jolley CS, Bissonette M, Bhattacharyya AK, et al. Chemoprevention of azoxymethane-induced colonic carcinogenesis by supplemental dietary ursodeoxycholic acid. Cancer Res. 1994;54:5071–4.
- Kohno H, Suzuki R, Yasui Y, Miyamoto S, Wakabayashi K, Tanaka T. Ursodeoxycholic acid versus sulfasalazine in colitis-related colon carcinogenesis in mice. Clin Cancer Res. 2007;13:2519–25. CrossRef
- Shah SA, Volkov Y, Arfin Q, Abdel-Latif MM, Kelleher D. Ursodeoxycholic acid inhibits interleukin 1 beta [corrected] and deoxycholic acid-induced activation of NF-kappaB and AP-1 in human colon cancer cells. Int J Cancer. 2006;118:532–9. CrossRef
- Tsagarakis NJ, Drygiannakis I, Batistakis AG, Kolios G, Kouroumalis EA. A concentration-dependent effect of ursodeoxycholate on apoptosis and caspases activities of HepG2 hepatocellular carcinoma cells. Eur J Pharmacol. 2010;640:1–7. CrossRef
- Feldman R, Martinez JD. Growth suppression by ursodeoxycholic acid involves caveolin-1 enhanced degradation of EGFR. Biochim Biophys Acta. 2009;1793:1387–94. CrossRef
- Martinez JD, Stratagoules ED, LaRue JM, Powell AA, Gause PR, Craven MT, et al. Different bile acids exhibit distinct biological effects: the tumor promoter deoxycholic acid induces apoptosis and the chemopreventive agent ursodeoxycholic acid inhibits cell proliferation. Nutr Cancer. 1998;31:111–8. CrossRef
- Costelli P, Carbo N, Tessitore L, Bagby GJ, Lopez-Soriano FJ, Argiles JM, et al. Tumor necrosis factor-alpha mediates changes in tissue protein turnover in a rat cancer cachexia model. J Clin Invest. 1993;92:2783–9. CrossRef
- Bauhofer A, Witte K, Celik I, Pummer S, Lemmer B, Lorenz W. Sickness behaviour, an animal equivalent to human quality of life, is improved in septic rats by G-CSF and antibiotic prophylaxis. Langenbecks Arch Surg. 2001;386:132–40. CrossRef
- Garioud A, Seksik P, Chretien Y, Corphechot C, Poupon R, Poupon RE, et al. Characteristics and clinical course of primary sclerosing cholangitis in France: a prospective cohort study. Eur J Gastroenterol Hepatol. 2010;22:842–7. CrossRef
- Sjoqvist U, Tribukait B, Ost A, Einarsson C, Oxelmark L, Lofberg R. Ursodeoxycholic acid treatment in IBD-patients with colorectal dysplasia and/or DNA-aneuploidy: a prospective, double-blind, randomized controlled pilot study. Anticancer Res. 2004;24:3121–7.
- Tisdale MJ. Catabolic mediators of cancer cachexia. Curr Opin Support Palliat Care. 2008;2:256–61. CrossRef
- Shiraki K, Ito T, Sugimoto K, Fuke H, Inoue T, Miyashita K, et al. Different effects of bile acids, ursodeoxycholic acid and deoxycholic acid, on cell growth and cell death in human colonic adenocarcinoma cells. Int J Mol Med. 2005;16:729–33.
- Byrne AM, Foran E, Sharma R, Davies A, Mahon C, O’Sullivan J, et al. Bile acids modulate the Golgi membrane fission process via a protein kinase Ceta and protein kinase D-dependent pathway in colonic epithelial cells. Carcinogenesis. 2010;31:737–44. CrossRef
- Pongracz J, Clark P, Neoptolemos JP, Lord JM. Expression of protein kinase C isoenzymes in colorectal cancer tissue and their differential activation by different bile acids. Int J Cancer. 1995;61:35–9. CrossRef
- Zhang X, Jin B, Huang C. The PI3K/Akt pathway and its downstream transcriptional factors as targets for chemoprevention. Curr Cancer Drug Targets. 2007;7:305–16. CrossRef
- von Haehling S, Morley JE, Coats AJ, Anker SD. Ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle. J Cachexia Sarcopenia Muscle. 2010;1:7–8.
About this Article
- Ursodeoxycholic acid treatment in a rat model of cancer cachexia
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Journal of Cachexia, Sarcopenia and Muscle
Volume 3, Issue 1 , pp 31-36
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Cancer cachexia
- Ursodeoxycholic acid
- Yoshida hepatoma animal model
- Author Affiliations
- 1. Applied Cachexia Research, Department of Cardiology, Charité Medical School, Berlin, Germany
- 2. Center for Cardiovascular Research, Charité Medical School, Campus Mitte, Hessische Str. 3-4, 10115, Berlin, Germany
- 3. Center for Stroke Research Berlin, Charité Medical School, Berlin, Germany
- 4. Centre for Clinical and Basic Research, IRCCS San Raffaele, Rome, Italy
- 5. Norwich Medical School, University of East Anglia, Norwich, UK