Dietary citrulline does not modify rat colon tumor response to chemotherapy, but failed to improve nutritional status.

During cancer therapy many patients experience significant malnutrition, leading to decreased tolerance to chemotherapy and decreased survival. Dietary citrulline supplementation improves nutritional status in situations such as short bowel syndrome and aging, and is of potential interest in oncology. However, a mandatory prerequisite is to test this amino acid for interaction with tumor growth and chemotherapy response. Dietary citrulline (Cit; 2%), or an isonitrogenous mix of non-essential amino acids (control), was given to Ward colon tumor-bearing rats the day before chemotherapy initiation. Chemotherapy included 2 cycles, one week apart, each consisting of one injection of CPT-11 (50 mg/kg) and of 5-fluorouracil (50 mg/kg) the day after. Body weight, food intake and tumor volume were measured daily. The day after the last injection, rats were killed, muscles (EDL, gastrocnemius), intestinal mucosa, tumor, spleen and liver were weighed. Muscle and intestinal mucosa protein content were measured. Phosphorylated 4E-BP1 was measured in muscle and tumor as a surrogate for biosynthetic activation. FRAPS (Ferric Reducing Ability of Plasma) and thiols in plasma, muscle and tumor were evaluated and plasma amino acids and haptoglobin were measured. Numerous parameters did not differ by diet overall: a) response of tumor mass to treatment, b) tumor antioxidants and phosphorylated 4E-BP1 levels, c) relative body weight and relative food intake, d) weight of EDL, gastrocnemius, intestinal mucosa, spleen and liver and e) plasma haptoglobin concentrations. Moreover, plasma citrulline concentration was not correlated to relative body weight, only cumulated food intake and plasma haptoglobin concentrations were correlated to relative body weight. Citrulline does not alter the tumor response to CPT-11/5FU based therapy but, has no effect on nutritional status, which could be due to the anorexia and the low amount of citrulline and protein ingested.

Short-term Effects of Diet and Activity Changes on Inflammation and Insulin Resistance.

The present study focused on rapid responses of inflammation markers and insulin resistance to dietary restriction and exercise in inactive patients. 13 obese women were included during a 5-day time frame during which decreases in food intake (-1 378±298 kcal) were associated with 2 exercise sessions (80 and 40 min). Circulating inflammatory biomarkers, insulin resistance index and muscle soreness were measured in fasted conditions. Fasting plasma concentrations of CRP and insulin resistance index decreased over the period (respectively, p=0.02 and p=0.01), concentrations of IL-6 and TNF-α appeared unchanged (p>0.05). Changes in IL-6 (enhanced) and TNF-α (reduced) concentrations following the prolonged exercise differed compared to days with 40 min exercise and days without exercise (p<0.05). Muscle soreness appeared higher after the 80 min than after the 40-min exercise (p=0.01), and were related with IL-6 and CRP concentration changes. A 5-day period combining exercise and diet reduced the insulin-resistance index and the CRP fasting concentrations. The 80-min exercise enhanced IL-6 and lowered TNF-α concentration changes while days without exercise unaffected these cytokines. These exercise effects on cytokines may have benefited to the insulin resistance index. The duration and number of the exercise sessions appeared sufficient for inactive subjects to initiate health benefits without inducing negative effects on inflammation and muscle soreness.

Citrulline and nitrogen homeostasis: an overview.

Citrulline (Cit) is a non-essential amino acid whose metabolic properties were largely ignored until the last decade when it began to emerge as a highly promising nutrient with many regulatory properties, with a key role in nitrogen homeostasis. Because Cit is not taken up by the liver, its synthesis from arginine, glutamine, ornithine and proline in the intestine prevents the hepatic uptake of the two first amino acids which activate the urea cycle and so prevents amino acid catabolism. This sparing effect may have positive spin-off for muscle via increased protein synthesis, protein content and functionality. However, the mechanisms of action of Cit are not fully known, even if preliminary data suggest an implication of mTOR pathway. Further exploration is needed to gain a complete overview of the role of Cit in the control of nitrogen homeostasis.