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

Abstract

Patients with metastatic triple negative breast cancer (TNBC) need new therapies to improve the low survival rates achieved with standard treatments. In this work, we show for the first time that the survival of mice with metastatic TNBC can be markedly increased by replacing their normal diet with artificial diets in which the levels of amino acids (AAs) and lipids are strongly manipulated. After observing selective anticancer activity in vitro, we prepared five artificial diets and evaluated their anticancer activity in a challenging model of metastatic TNBC. The model was established by injecting 4T1 murine TNBC cells into the tail vein of immunocompetent BALB/cAnNRj mice. First-line drugs doxorubicin and capecitabine were also tested in this model. AA manipulation led to modest improvements in mice survival when the levels of lipids were normal. Reducing lipid levels to 1% markedly improved the activity of several diets with different AA content. Some mice fed the artificial diets as monotherapy lived much longer than mice treated with doxorubicin and capecitabine. An artificial diet without 10 non-essential AAs, with reduced levels of essential AAs, and with 1% lipids improved the survival not only of mice with TNBC but also of mice with other types of metastatic cancers.

Dietary Manipulation of Amino Acids for Cancer Therapy

“…Under these new environments, the DNA aberrations of cancer cells may cause their death [54]. Based on this idea, we evaluated the therapeutic potential of numerous artificial diets in mice with different types of metastatic cancers [26,27,119,343]. As discussed in the previous section, some of the diets induced higher survival rates in mice with metastatic cancer than those achieved with the standard pharmacological treatments, and one of the diets is currently being tested (in monotherapy) in patients with different types of metastatic cancers.…”

“…Importantly, these unfavorable environments can be created with different types of diets, and a new metabolic environment may be toxic to cancer cells with different sets of mutations [54]. This would explain why different diets induce antitumor activity in the same cancer type, and why the same diet can be active in different types of cancer [343].…”

“…The increase in αKG concentration led to the hypomethylation of H3K4me3, thereby suppressing the epigenetically activated oncogenic pathways in melanoma [342]. Our recent investigation revealed that supplementing specific artificial diets with Gln can increase their anticancer activity in mice with metastatic cancers; most of our active diets contained 5-6% Gln in their composition [26,27,343]. Therefore, although Gln plays a key role in cancer cell metabolism, anticancer activity can be achieved by both restricting and supplementing this AA.…”

“…Mice fed with the artificial diets as monotherapy lived longer than mice treated with the first-line drugs doxorubicin and capecitabine. An artificial diet without 10 NEAAs, with reduced levels of EAAs and 1% lipids, improved the survival not only of mice with TNBC, but also of mice with other types of metastatic cancers [343]. Two additional diets with altered levels of sulfur AAs also improved the survival of mice with metastatic colon cancer, ovarian cancer, and renal cell carcinomas [119].…”

“…We recently reported that the manipulation of multiple AAs simultaneously induced marked anticancer activities in mice with different types of metastatic cancers [26,27,119,343]. We screened 18 artificial diets for anticancer activity in mice with disseminated renal cell carcinomas and observed that mice fed with a diet lacking in six AAs (Ser, Cys, Tyr, Pro, Asn, and Glu) lived longer than mice treated with sunitinib or anti-PD-1 immunotherapy (which are standard therapies for patients with metastatic renal cell carcinomas).…”