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A Diet Rich in Fish Oil and Leucine Ameliorates Hypercalcemia in Tumour-Induced Cachectic Mice

Division of Human Nutrition and Health, Wageningen University, 6700 EV Wageningen, The Netherlands
Danone Nutricia Research, Nutricia Advanced Medical Nutrition, 3584 CT Utrecht, The Netherlands
Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, 08193 Barcelona, Spain
Department of Clinical Medicine, University La Sapienza, 185 Rome, Italy
NUTRIM School of Nutrition and Translational Research in Metabolism, Faculty of Health, Medicine, and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(20), 4978;
Received: 8 August 2019 / Revised: 19 September 2019 / Accepted: 26 September 2019 / Published: 9 October 2019
(This article belongs to the Special Issue Cancer Cachexia and Related Metabolic Dysfunction)
Background: Dietary supplementation with leucine and fish oil rich in omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) has previously been shown to reduce cachexia-related outcomes in C26 tumour-bearing mice. To further explore associated processes and mechanisms we investigated changes in plasma Ca2+ levels, the involvement of parathyroid hormone related protein (PTHrP), and its possible interactions with cyclooxygenase 2 (COX-2). Methods: CD2F1 mice were subcutaneously inoculated with C26 adenocarcinoma cells or sham treated and divided in: (1) controls, (2) tumour-bearing controls, and (3) tumour-bearing receiving experimental diets. After 20 days, body and organ masses and total plasma Ca2+ levels were determined. Furthermore, effects of DHA, EPA and leucine on production of PTHrP were studied in cultured C26 cells. Results: The combination of leucine and fish oil reduced tumour-associated hypercalcemia. Plasma Ca2+ levels negatively correlated with carcass mass and multiple organ masses. DHA was able to reduce PTHrP production by C26 cells in vitro. Results indicate that this effect occurred independently of COX-2 inhibition. Conclusion: Our results suggest that cancer-related hypercalcemia may be ameliorated by a nutritional intervention rich in leucine and fish oil. The effect of fish oil possibly relates to a DHA-induced reduction of PTHrP excretion by the tumour. View Full-Text
Keywords: hypercalcemia; PTHrP; cachexia; fish oil; leucine hypercalcemia; PTHrP; cachexia; fish oil; leucine
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MDPI and ACS Style

Plas, R.L.C.; Poland, M.; Faber, J.; Argilès, J.; van Dijk, M.; Laviano, A.; Meijerink, J.; Witkamp, R.F.; van Helvoort, A.; van Norren, K. A Diet Rich in Fish Oil and Leucine Ameliorates Hypercalcemia in Tumour-Induced Cachectic Mice. Int. J. Mol. Sci. 2019, 20, 4978.

AMA Style

Plas RLC, Poland M, Faber J, Argilès J, van Dijk M, Laviano A, Meijerink J, Witkamp RF, van Helvoort A, van Norren K. A Diet Rich in Fish Oil and Leucine Ameliorates Hypercalcemia in Tumour-Induced Cachectic Mice. International Journal of Molecular Sciences. 2019; 20(20):4978.

Chicago/Turabian Style

Plas, Rogier L.C., Mieke Poland, Joyce Faber, Josep Argilès, Miriam van Dijk, Alessandro Laviano, Jocelijn Meijerink, Renger F. Witkamp, Ardy van Helvoort, and Klaske van Norren. 2019. "A Diet Rich in Fish Oil and Leucine Ameliorates Hypercalcemia in Tumour-Induced Cachectic Mice" International Journal of Molecular Sciences 20, no. 20: 4978.

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