Specificity of the suppression of metastatic phenotype by tyrosine and phenylalanine restriction

Abstract

Amino acid restriction modulates tumor growth, although effects on metastasis are poorly documented. We demonstrate that low levels of tyrosine (Tyr) and phenylalanine (Phe) suppress metastasis of B16-BL6 melanoma and that these effects are specific to these two amino acids. Weight loss and sustained low body weight in mice fed low Tyr and Phe diet do not contribute to the antimetastatic effects. Furthermore, methionine (Met) restriction, which decreased survival of mice inoculated i.p. with B16 melanoma, only slightly inhibited spontaneous metastasis compared to the dramatic inhibition during Tyr and Phe restriction. Tyr and Phe restriction inhibited spontaneous metastasis by impairing the ability of tumor cells to establish metastatic foci and not via differential tumor cell removal from the blood. Spontaneous metastasis is blocked by Tyr and Phe intervention even in mice with established lymph node tumors. Tumors isolated from mice fed low Tyr and Phe diet reinoculated into mice fed normal diet exhibited lower experimental metastatic potential, reflected by decreased formation of lung tumor colonies and increased survival of inoculated mice. This decrease in metastatic potential is not associated with tumor chemosensitivity. These findings indicate that Tyr and Phe restriction could become an important adjuvant to effective melanoma treatment.

Alcohol consumption suppresses metastasis of B16-BL6 melanoma in mice

“…(P < 0.05). The weight lost by this group should not influence metastasis, since we previously reported that forcing mice to lose 2 g through restriction of food intake does not affect spontaneous metastasis of B16-BL6 melanoma [20].…”

Specific Amino Acid Dependency Regulates Invasiveness and Viability of Androgen-Independent Prostate Cancer Cells

“…Perhaps the most effective use of selective amino acid restriction in addition to the inherent anti-invasive and pro-apoptotic responses, is in enhancement of other therapeutic agents. For example, we found that dietary restriction of Tyr/Phe enhances the experimental chemotherapy against murine melanoma in vivo (58,(63)(64)(65). Restriction of these amino acids also prevents the emergence of drug resistance during chemotherapy (64) and sensitizes adriamycin-resistant P388 leukemia cells to chemotherapy in vitro (66).…”

Experimental metastasis and differentiation of murine melanoma cells: actions and interactions of factors affecting different intracellular signalling pathways

“…There are many other possibilities, including the two-fold difference in concentration of a biological factor(s) from serum, or the higher concentrations of tyrosine and phenylalanine in DMEM. These two melanin precursors appear to have more than a substrate effect in stimulation of melanogenesis [24], and their dietary intake can affect the metastasis of murine melanoma cells in vivo [26]. Prezioso et al [11] found, however, that added tyrosine and phenylalanine alone did not affect the EMP of B16 cells greatly, and that cellular cAMP content and gamma-glutamyltranspeptidase activity (both possibly relevant to metastasis) were slightly higher after growth in DMEM than in RPMI 1640 medium.…”

“…Surprisingly, nearly all tested inducers of differentiation increased rather than decreased the EMP of B16 melanoma sublines. Similarly, retinoic acid supplementation or tyrosine restriction, treatments that decrease pigmentation of B16 cells [23,24], also decrease their metastatic potential [25,26]. Conversely, growth with interferon-y sometimes inhibited B16 cell differentiation and usually increased the EMP, and exposure to ol-MSH reduced the EMP of more-pigmented melanoma lines [19].…”