Bioactive properties and clinical safety of a novel milk protein peptide

Richard B Kreider, Mike Iosia, Matt Cooke, Geoffrey Hudson, Chris Rasmussen, Helen Chen, Olof Mollstedt, Men-Hwei Tsai, Richard B Kreider, Mike Iosia, Matt Cooke, Geoffrey Hudson, Chris Rasmussen, Helen Chen, Olof Mollstedt, Men-Hwei Tsai

Abstract

Background: Milk protein fractions and peptides have been shown to have bioactive properties. This preliminary study examined the potential mechanisms of action and clinical safety of novel milk protein peptide (MP).

Findings: A novel MP mixture inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 2 (VEGFR2), and insulin receptor (IR) with IC50 of 9.85 μM, 7.7 μM, and 6.18 μM respectively. In vitro, this multi-kinase inhibitor causes apoptosis in HT-29 colon cancer cells, and in a C. elegans worm study, showed a weak but significant increase in lifespan. A six week double-blind, placebo-controlled study involving 73 healthy volunteers demonstrated that the MP mixture is safe to consume orally. All clinical blood markers remained within normal levels and no clinically significant side effects were reported. There was some evidence of improved insulin sensitivity, neutrophil-to-lymphocyte ratio (NLR), and quality of life assessment of role of physical function.

Conclusions: These data in combination with the observed in vitro anti-cancer properties warrant further clinical studies to investigate this MP mixture as a potential clinical nutrition intervention for improving the quality of life and clinical outcomes in cancer patients.

Trial registration: NCT01412658.

Figures

Figure 1
Figure 1
Determination of tyrosine kinase inhibitory properties of novel milk peptide mixture MP. The novel milk peptide mixture was screened against a panel of kinases. Specifically, the IC50 for inhibition of epidermal growth factor receptor (EGFR), insulin receptor (IR), and vascular epidermal growth factor receptor-2 (VEGFR2) were determined using a 10-point dose response radiolabeled assay.
Figure 2
Figure 2
Comparison of HT-29 human colon cancer cell death between commercially available whey peptides and the MP mixture. HT-29 colon cancer cells were incubated with 0.68 μg/μl concentration of commercial hydrolyzed whey protein, MP peptides, and vehicle only (control). Pictures were taken after 20 hours of incubation.
Figure 3
Figure 3
MP fed C. elegans worms have a weak but significant increase in life-span. -- represents survival of wild-type (N2) animals fed with standard agar; --- represents survival of wild-type animals fed with agar containing 20 μg/ml peptides. Control: n = 40, m = 13; Milk peptides (MP): n = 40, m = 15 (P = 0.0136). n represents the number of animals observed in each experiment. m represents the median adult life span.
Figure 4
Figure 4
Neutrophil to lymphocyte ratio values observed for the placebo (P) and milk protein (MP) groups over time.
Figure 5
Figure 5
Change in hormonal responses from baseline observed for the placebo (P) and milk protein (MP) groups. HOMAIR represents homeostatic model assessment of insulin resistance.
Figure 6
Figure 6
Comparison between placebo and MP group in role physical measure of quality of life.

References

    1. Nagpal R, Behare P, Rana R, Kumar A, Kumar M, Arora S, Morotta F, Jain S, Yadav H. Bioactive peptides derived from milk proteins and their health beneficial potentials: an update. Food Funct. 2011;2:18–27. doi: 10.1039/c0fo00016g.
    1. Lien E, Jackson J, Kuhlman C, Pramuk K, Lonnerdal B, Janszen D. Variations in concentrations of lactoferrin in human milk: a nine country survey. Adv Exp Med Biol. 2004;554:423–426.
    1. Domellof M, Hemell O, Dewey KG, Cohen RJ, Lonnerdal B. Factors influencing concentrations of iron, zinc, and copper in human milk. Adv Exp Med Biol. 2004;554:355–358.
    1. Kaminsky LA, Bryant CX, Mahler DA, Durstine JL, Humphrey RH. ACSM's Guidelines for Exercise Testing and Prescription. 8. Baltimore, MD: Lippincott, Williams & Wilkins; 2009.
    1. Cuka S, Dvornik S, Drazenovic K, Mihic J. Evaluation of the Dade Behring Dimension RxL clinical chemistry analyzer. Clin Lab. 2001;47:35–40.
    1. McAuley KA, Williams SM, Mann JI, Walker RJ, Lewis-Barned NJ, Temple LA, Duncan AW. Diagnosing insulin resistance in the general population. Diabetes Care. 2001;24:460–464. doi: 10.2337/diacare.24.3.460.
    1. Ware JE Jr, Kosinski M, Bayliss MS, McHorney CA, Rogers WH, Raczek A. Comparison of methods for the scoring and statistical analysis of SF-36 health profile and summary measures: summary of results from the Medical Outcomes Study. Med Care. 1995;33:AS264–279.
    1. Lonnerdal B. Nutritional and physiologic significance of human milk proteins. Am J Clin Nutr. 2003;77:1537S–1543S.
    1. Lonnerdal B. Human milk proteins: key components for the biological activity of human milk. Adv Exp Med Biol. 2004;554:11–25.
    1. Jain A, Lense S, Linehan JC, Raugei S, Cho H, DuBois DL, Shaw WJ. Incorporating peptides in the outer-coordination sphere of bioinspired electrocatalysts for hydrogen production. Inorg Chem. 2011;50:4073–4085. doi: 10.1021/ic1025872.
    1. Korhonen H, Pihlanto A. Food-derived bioactive peptides--opportunities for designing future foods. Curr Pharm Des. 2003;9:1297–1308. doi: 10.2174/1381612033454892.
    1. Vermeirssen V, Van Camp J, Verstraete W. Bioavailability of angiotensin I converting enzyme inhibitory peptides. Br J Nutr. 2004;92:357–366. doi: 10.1079/BJN20041189.
    1. Phelan M, Kerins D. The potential role of milk-derived peptides in cardiovascular disease. Food Funct. 2011;2:153–167. doi: 10.1039/c1fo10017c.
    1. Drouet L, Bal Dit Sollier C, Mazoyer E, Levy-Toledano S, Jolles P, Fiat A. Use of k- caseinoglycopeptide for preparation of composition, especially a drug, for prevention and treatment of thrombosis. 1990. EP0397571.
    1. Drouet L, Bal Dit Sollier C, Mazoyer E, Levy-Toledano S, Jolles P, Fiat A. Method of preventing or treating thrombosis using kappa-caseinoglycopeptide as active ingredient. 1990. US5063203.
    1. Khazaie K, Schirrmacher V, Lichtner RB. EGF receptor in neoplasia and metastasis. Cancer Metastasis Rev. 1993;12:255–274. doi: 10.1007/BF00665957.
    1. Lurje G, Lenz HJ. EGFR signaling and drug discovery. Oncology. 2009;77:400–410. doi: 10.1159/000279388.
    1. Okamoto K, Okamoto I, Okamoto W, Tanaka K, Takezawa K, Kuwata K, Yamaguchi H, Nishio K, Nakagawa K. Role of survivin in EGFR inhibitor-induced apoptosis in non-small cell lung cancers positive for EGFR mutations. Cancer Res. 2010;70:10402–10410. doi: 10.1158/0008-5472.CAN-10-2438.
    1. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature. 1993;366:461–464. doi: 10.1038/366461a0.
    1. Baumeister R, Schaffitzel E, Hertweck M. Endocrine signaling in Caenorhabditis elegans controls stress response and longevity. J Endocrinol. 2006;190:191–202. doi: 10.1677/joe.1.06856.
    1. Chua W, Charles KA, Baracos VE, Clarke SJ. Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer. Br J Cancer. 2011;104:1288–1295. doi: 10.1038/bjc.2011.100.
    1. Ding PR, An X, Zhang RX, Fang YJ, Li LR, Chen G, Wu XJ, Lu ZH, Lin JZ, Kong LH. et al.Elevated preoperative neutrophil to lymphocyte ratio predicts risk of recurrence following curative resection for stage IIA colon cancer. Int J Colorectal Dis. 2010;25:1427–1433. doi: 10.1007/s00384-010-1052-0.
    1. Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ. Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol. 2005;91:181–184. doi: 10.1002/jso.20329.
    1. Brekken RA, Thorpe PE. Vascular endothelial growth factor and vascular targeting of solid tumors. Anticancer Res. 2001;21:4221–4229.
    1. Shibuya M. Vascular endothelial growth factor (VEGF)-Receptor2: its biological functions, major signaling pathway, and specific ligand VEGF-E. Endothelium. 2006;13:63–69. doi: 10.1080/10623320600697955.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren