A mixture of amino acids and other small molecules present in the serum suppresses the growth of murine and human tumors <i>in vivo</i>

Kulcsár, Gyula; Gaál, D.; Kulcsár, Péter István; Schulcz, Ákos; Czömpöly, Tamás

doi:10.1002/ijc.27756

Cited by 9 publications

(8 citation statements)

References 33 publications

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“…We found that treatment of tumor-bearing mice with an MAA oral supplement inhibited the growth of sarcomas by 40%–69%. In agreement, previous research indicated that a mixture of amino acids with 5-fluorouracil or cisplatin led to enhanced tumor inhibition through the mitochondrial apoptosis pathway and to G1 arrest in cancer cells [ 9 ]. Moreover, Besirli et al [ 27 ] found that activation of autophagy in injured photoreceptor cells inhibited fas-mediated apoptosis.…”

Section: Discussionsupporting

confidence: 87%

“…Autophagy, a lysosomal degradation pathway, is inhibited by the interaction of cellular Bcl-2 with a key autophagy effector, Beclin-1 [ 26 ]. Kulcsár et al [ 9 ] hypothesized that the small molecules that selectively accumulate in cancer cells might participate in a non-immunological antitumor surveillance mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…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 . In cancer patients, 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 ].…”

Section: Introductionmentioning

confidence: 99%

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Soy-Based Multiple Amino Acid Oral Supplementation Increases the Anti-Sarcoma Effect of Cyclophosphamide

et al. 2016

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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.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Soy-Based Multiple Amino Acid Oral Supplementation Increases the Anti-Sarcoma Effect of Cyclophosphamide

et al. 2016

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“…57,58 In addition, studies of the metabolic transformation of labeled PN by hepatoma cells growing in rats led to the identification of a novel vitamin B6 metabolite, adenosine-N6-diethylthioether N1-pyridoximine 5 0 -phosphate. 59 Since then, additional reports based on in vitro and in vivo observations have been published to support the hypotheses that (1) vitamin B6 would per se promote antiproliferative or cytotoxic effects on cancer cells, [60][61][62][63][64][65] and (2) vitamin B6 would synergize with other micronutrients, 66,67 tumor necrosis factor stimulation 68 and hypertriglyceridemia 69 in exerting antineoplastic effects. In the late 1990s, Rosenthal 70 reported prominent antitumor effects for L-canaline, a structural analog of L-ornithine that covalently inactivates PLP-dependent enzymes.…”

Section: Preclinical Observationsmentioning

confidence: 99%

Effects of vitamin B6 metabolism on oncogenesis, tumor progression and therapeutic responses

et al. 2013

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Pyridoxal-5'-phosphate (PLP), the bioactive form of vitamin B6, reportedly functions as a prosthetic group for >4% of classified enzymatic activities of the cell. It is therefore not surprising that alterations of vitamin B6 metabolism have been associated with multiple human diseases. As a striking example, mutations in the gene coding for antiquitin, an evolutionary old aldehyde dehydrogenase, result in pyridoxine-dependent seizures, owing to the accumulation of a metabolic intermediate that inactivates PLP. In addition, PLP is required for the catabolism of homocysteine by transsulfuration. Hence, reduced circulating levels of B6 vitamers (including PLP as well as its major precursor pyridoxine) are frequently paralleled by hyperhomocysteinemia, a condition that has been associated with an increased risk for multiple cardiovascular diseases. During the past 30 years, an intense wave of clinical investigation has attempted to dissect the putative links between vitamin B6 and cancer. Thus, high circulating levels of vitamin B6, as such or as they reflected reduced amounts of circulating homocysteine, have been associated with improved disease outcome in patients bearing a wide range of hematological and solid neoplasms. More recently, the proficiency of vitamin B6 metabolism has been shown to modulate the adaptive response of tumor cells to a plethora of physical and chemical stress conditions. Moreover, elevated levels of pyridoxal kinase (PDXK), the enzyme that converts pyridoxine and other vitamin B6 precursors into PLP, have been shown to constitute a good, therapy-independent prognostic marker in patients affected by non-small cell lung carcinoma (NSCLC). Here, we will discuss the clinical relevance of vitamin B6 metabolism as a prognostic factor in cancer patients.

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“…Indeed, this has been shown by several publications [ 7 , 8 ]. However, an amino acid-rich substrate could inhibit tumor growth by cell cycle arrest and initiation of apoptosis in a murine model [ 9 ]. These contradictory findings may well represent a dose-dependent effect, rendering both the “depletion” and the “overload” model valid.…”

Section: Introductionmentioning

confidence: 99%

Tumor-dependent increase of serum amino acid levels in breast cancer patients has diagnostic potential and correlates with molecular tumor subtypes

et al. 2013

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BackgroundMalignancies induce changes in the levels of serum amino acids (AA), which may offer diagnostic potential. Furthermore, changes in AA levels are associated with immune cell function. In this study, serum AA levels were studied in breast cancer patients versus patients with benign breast lesions.MethodsIn a prospective study, serum levels of 15 AA were measured by high performance liquid chromatography before and after surgery in 41 breast cancer patients (BrCA) and nine patients with benign breast lesions (healthy donors, HD). Results were analyzed in relation to clinical tumor data and tested against immunological flow cytometry data. Principal component analysis was performed and the accuracy of AA levels as a potential diagnostic tool was tested.ResultsPre- but not postoperative serum AA levels were increased in BrCA in eight out of 15 AA compared with HD. Serum AA levels were highest in the most aggressive (basal-like) as compared with the least aggressive tumor subtype (luminal A). A principal component (PC1) of all measured AA correlated with a mainly pro-inflammatory immune profile, while a second one (PC2, selectively considering AA preoperatively differing between HD and BrCA) could predict health state with an area under the curve of 0.870.ConclusionsBreast cancer shows a tumor-dependent impact on serum AA levels, which varies with intrinsic tumor subtypes and is associated with a pro-inflammatory state. Serum AA levels need further evaluation as a potential diagnostic tool.

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A mixture of amino acids and other small molecules present in the serum suppresses the growth of murine and human tumors in vivo

Cited by 9 publications

References 33 publications

Soy-Based Multiple Amino Acid Oral Supplementation Increases the Anti-Sarcoma Effect of Cyclophosphamide

Soy-Based Multiple Amino Acid Oral Supplementation Increases the Anti-Sarcoma Effect of Cyclophosphamide

Effects of vitamin B6 metabolism on oncogenesis, tumor progression and therapeutic responses

Tumor-dependent increase of serum amino acid levels in breast cancer patients has diagnostic potential and correlates with molecular tumor subtypes

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