Abstract
The use of a mixture of amino acids caused a selective apoptosis induction against a variety of tumor cell lines, reduced the adverse effects of anti-cancer drugs and increased the sensitivity of tumor cells to chemotherapeutic agents. We evaluated the effects and underlying mechanisms of soy-derived multiple amino acids’ oral supplementation on the therapeutic efficacy of low-dose cyclophosphamide (CTX) and on tumor growth, apoptosis, and autophagy in severe combined immunodeficiency (SCID) mice that were injected with sarcoma-180 (S-180) cells. 3-methyladenine or siRNA knockdown of Atg5 was used to evaluate its effect on sarcoma growth. A comparison of mice with implanted sarcoma cells, CTX, and oral saline and mice with implanted sarcoma cells, CTX, and an oral soy-derived multiple amino acid supplement indicated that the soy-derived multiple amino acid supplement significantly decreased overall sarcoma growth, increased the Bax/Bcl-2 ratio, caspase 3 expression, and apoptosis, and depressed LC3 II-mediated autophagy. Treatment with 3-methyladenine or Atg5 siRNA elicited similar responses as CTX plus soy-derived multiple amino acid in downregulating autophagy and upregulating apoptosis. A low dose of CTX combined with an oral soy-derived multiple amino acid supplement had a potent anti-tumor effect mediated through downregulation of autophagy and upregulation of apoptosis.
Highlights
The main anti-tumor therapies are surgery, radiotherapy, immunotherapy, and chemotherapy. the synthetic anti-neoplastic agents used for chemotherapy have potent effects, they can cause severe adverse effects and lead to multiple drug resistance
For mice with tumors that were given CTX, tumor growth was significantly less for mice given oral multiple amino acids (MAA) (Group D) than for mice given oral saline, and this effect was dose-dependent in terms of tumorNutrients weight (D1.0ˆ and D2.0ˆ groups) and tumor weight/body weight7 of(D2.0ˆ
We evaluated the effect of low-dose CTX combined with an oral MAA supplement on a well-established sarcoma model in mice
Summary
The main anti-tumor therapies are surgery, radiotherapy, immunotherapy, and chemotherapy. A specific nutrient supplement containing lysine, proline, arginine, ascorbic acid, and green tea extract ameliorated the progression of N-methyl-N-nitrosourea-induced mammary tumors [8]. Kulcsár et al [9] demonstrated that a mixture of amino acids and other substances (including L-arginine, L-histidine, L-methionine, L-phenylalanine, L-tyrosine, L-tryptophan, L-ascorbate, D-biotin, pyridoxine, riboflavin, adenine, L-malate) had a selective in vitro toxic effect against a variety of tumor cell lines, and that this active mixture selectively induced the apoptosis of cancer cells in vitro. Nutrients 2016, 8, 192 the use of dietary nutritional supplements can reduce the adverse effects of anti-cancer drugs [10] and increase the sensitivity of tumor cells to chemotherapeutic agents [4]. Nutritional supplements may mediate a “cross-talk” between apoptosis and autophagy and thereby promote or inhibit tumor progression, this has not yet been demonstrated. We directly examined the effect of the MAA formula on anti-tumor activity by use of in vitro and in vivo experiments
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