Artificial Diets Based on Selective Amino Acid Restriction versus Capecitabine in Mice with Metastatic Colon Cancer

Abstract

New therapies are needed to improve the low survival rates of patients with metastatic colon cancer. Evidence suggests that amino acid (AA) restriction can be used to target the altered metabolism of cancer cells. In this work, we evaluated the therapeutic potential of selective AA restriction in colon cancer. After observing anticancer activity in vitro, we prepared several artificial diets and evaluated their anticancer activity in two challenging animal models of metastatic colon cancer. These models were established by injecting CT26.WT murine colon cancer cells in the peritoneum (peritoneal dissemination) or in the tail vein (pulmonary metastases) of immunocompetent BALB/cAnNRj mice. Capecitabine, which is a first-line treatment for patients with metastatic colon cancer, was also evaluated in these models. Mice fed diet TC1 (a diet lacking 10 AAs) and diet TC5 (a diet with 6% casein, 5% glutamine, and 2.5% leucine) lived longer than untreated mice in both models; several mice survived the treatment. Diet TC5 was better than several cycles of capecitabine in both cancer models. Cysteine supplementation blocked the activity of diets TC1 and TC5, but cysteine restriction was not sufficient for activity. Our results indicated that artificial diets based on selective AA restriction have therapeutic potential for colon cancer.

Manipulation of Amino Acid Levels with Artificial Diets Induces a Marked Anticancer Activity in Mice with Renal Cell Carcinoma

“…Diet T2 (which lacks Cys, Asn, Pro, Tyr, Glu, and Ser, and contains high levels of Gln and Leu) showed the highest survival improvements in the animals. Diet T18 (a casein-based diet that contains low levels of all AAs except Gln and Leu) also showed anticancer activity in mice with renal cell carcinoma (this work), and in mice with colon cancer [45] and other types of metastatic cancers (our unpublished data). The efficacy and safety of an artificial diet based on diet T18 are currently being evaluated in patients with metastatic cancers in which the standard therapies have failed.…”

“…Diet T14 also induced a marked anticancer activity without causing weight loss in the animals (Figure 9). Diet T18, which induced a high anticancer activity in mice with metastatic colon cancer (diet TC5) [45], also showed activity in mice with renal cell carcinoma (Table 6 and Figure 11). However, only 1 of the 10 mice treated with diet T18 showed a remarkable anticancer response.…”

“…The normal diet of cancer patients would be temporally replaced with an artificial diet in which the levels of AAs and other nutrients are precisely controlled. An artificial diet based on diet T18, which has also shown marked activity in mice with other types of metastatic cancers [45], is currently being evaluated as monotherapy in a pilot clinical study in patients with different types of metastatic cancers. Blood tests in these patients will shed light on the metabolic changes elicited by our artificial diets.…”

“…Finally, we evaluated the anticancer activity of diet T18, which consisted of adding 5% Gln to diet T17 (Table 2); Gln is involved in the cellular transport of Leu and in the biosynthesis of NEAA [44]. We have recently reported that diet T18 (also known as TC5) induces a marked anticancer activity in mice with metastatic colon cancer [45]. Treatments began 7 days after the inoculation of 150 000 Renca cancer cells into the peritoneum of immunocompetent BALB/c mice.…”

Artificial Diets with Selective Restriction of Amino Acids and Very Low Levels of Lipids Induce Anticancer Activity in Mice with Metastatic Triple-Negative Breast Cancer

“…Artificial media lacking AAs were prepared as described previously [51,52]. Briefly, powdered DMEM medium without AAs (D9800-13; US Biological) was supplemented with sodium bicarbonate (Panreac, 141638.1211), glucose (Panreac, 141341.1211), FBS, penicillin/streptomycin and specific AAs (see Table 1).…”