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

Abstract

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.

Leucine Supplementation in Cancer Cachexia: Mechanisms and a Review of the Pre-Clinical Literature

“…Similarly, short-term light aerobic exercise combined with a leucine-rich diet (18% protein plus 3% leucine) resulted in reduced tumor weight and improved protein metabolism [ 129 ]. A leucine-rich diet combined with fish oil supplementation was found to improve tumor-induced hypercalcemia in male C26 tumor-bearing mice [ 138 ]. This is important, as hypercalcemia can result in muscle weakness and cardiac arrhythmias [ 139 , 140 ].…”

“…A few of the identified studies focus on the potential positive immune-modulatory effects of leucine supplementation during CC [ 124 , 138 , 141 ]. Faber et al used male C26 tumor-bearing mice to examine the impact of a specific nutritional combination (high protein, fish oil, leucine, and oligosaccharides), and its individual components, on inflammatory status and immune function during CC [ 141 ].…”

“…No effect on relative number of granulocytes, monocytes, or T cells was observed [ 141 ]. Plas et al explored inflammatory mediator levels in male C26 tumor-bearing mice subjected to leucine-rich feeding combined with fish oil supplementation [ 138 ]. Plasma PGE-2 and tumor PTHrP levels were reduced in tumor-bearing animals fed an enriched diet [ 138 ].…”

Targeting peripheral immune organs with self-assembling prodrug nanoparticles ameliorates allogeneic heart transplant rejection

“…Moreover, DHA was chosen as a molecular decorator, which has also been associated with anti‐tumor properties 35 . Furthermore, Omega‐3 (n‐3) PUFAs, especially eicosapentaenoic acid and DHA, are considered to have anti‐inflammatory properties and have been approved for the treatment of cancer cachexia 36 . Therefore, DPNP theoretically exerts anti‐rejection effects and also may greatly benefit transplant recipients with a diagnosis of malignancy, for example, in the setting of liver transplant for liver cancer.…”

Cancer Cachexia and Related Metabolic Dysfunction

“…Even though the pathogenesis of cancer cachexia is not fully understood, several candidates to prevent the loss of muscle and fat mass have been tested in experimental studies, including leucine and fish oil [114], rosiglitazone (insulin sensitizer) [115], activin receptor type 2 blockers [116], trimetazidine (exercise mimetic) [117], bortezomib (NF-κB inhibitor) [118], and vitamin D supplementation [119].…”