Antimetastasis effects of biocompounds in apple have been studied by our group. Our results have indicated that phloretin is an inhibitor of GLUT2 41) and that targeting GLUT2 significantly inhibited COLO 205 colon cancer cell proliferation, migration, and invasion in vitro and in vivo 42). In this study 43), p53-mediated signals were important. Inhibition of the wild-type p53 by dominant negative p53 will attenuate the phloretin-induced colon cancer migration and its related signals. In colorectal cancers, studies have demonstrated that the activation of nuclear factor-κB (NF-κB) occurs via lipopolysaccharide (LPS) binding to the Toll-like receptor 4 (TLR4). Modification of polysaccharide components in apple altered the LPS/TLR4/NF-κB pathway; consequently, supplementation of apple polysaccharide significantly inhibited the migratory ability in vitro on the LPS/TLR4/NF-κB pathway in colorectal cancer cells (HT-29 and SW620 cells) 44). In a study on liver cancer cells, the effect of apple polyphenol extract on the proliferation and invasion of rat ascites hepatoma cell line (AH109A) was examined in vitro. The apple polyphenol extract suppressed both proliferation and invasion of the hepatoma cell line in a dose-dependent manner up to 200 μg/mL. In an in vivo study, apple polyphenol also reduced the growth and metastasis of solid hepatomas and significantly suppressed the serum lipid peroxide level in rats transplanted with AH109A 45).
Apple polyphenols induced apoptotic cancer cell death Previous results demonstrated that apple polyphenol phloretin (50–150μM) significantly potentiates paclitaxel (10nM)-induced DNA laddering formation in Hep G2 cells. It was also demonstrated that the caspases 3, 8, and 9 were involved in apoptosis, as evidenced by activity assays 46). Previous studies in this area have also demonstrated that phloretin inhibited leukemia cell growth 47) and induced apoptosis of melanoma cells through deprivation of glucose uptake by inhibition of glucose transmembrane transport 48). Using 18F-fluorodeoxyglucose micropositron emission tomography the effects of phloretin-induced suppression of liver tumor growth were demonstrated to involve regulation of glucose transportation. The 18F-fluorodeoxyglucose uptake in the phloretin-treated Hep G2 tumor-bearing mice was significantly suppressed as compared with the control mice. Effects of phloretin on glioblastoma cancer cells have been investigated via induction of apoptosis and cells’ growth cycle arrest. The identified mechanisms demonstrated increased expression of p27 and decreased expression of cdk2, cdk4, cdk6, cyclin D, and cyclin E. Moreover, the phosphatidylinositol-3-kinase/Akt and the mammalian target of rapamycin (PI3K/Akt/mTOR) signaling cascades were suppressed by phloretin in a dose-dependent manner 49). Phloretin-based combination treatment enhanced the anticancer effects of cisplatin on nonsmall cell lung cancer cell lines by suppressing the expression of Bcl-2, increasing the protein expression of cleaved caspases 3 and 9, and deregulating the expression of matrix metalloproteinase-2 and metalloproteinase-9 on gene and protein levels 50). The results suggest that inhibition of intracellular glucose uptake was the most important mechanism responsible for the cancer cell killing effects. Because many cancer cells rely on aerobic glycolysis for energy production, Xintaropoulou et al 51) targeted this pathway as a potential strategy to inhibit cancer cell growth. In that study, inhibition of five glycolysis pathway molecules (GLUT1, HKII (hexokinase II), PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3), PDHK1 (pyruvate dehydrogenase kinase I), and LDH (lactate dehydrogenase)) using nine inhibitors (phloretin, quercetin, STF31 (Glut1 inhibitor), WZB117 (Glut1 inhibitor), 3PO (3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one, glycolytic inhibitor), 3-bromopyruvate, dichloroacetate, oxamic acid, NHI-1 (lactate dehydrogenase A inhibitor)) was investigated in panels of breast and ovarian cancer cell line models. Their results indicated that growth of breast and ovarian cancer cell lines was more sensitive to the glycolytic pathway, with increased sensitivity to the inhibitors under normoxic conditions 52).
Signaling molecules and disease protection effects of phloretin
As described earlier, apple polyphenols induced anticancer activity mainly through their antioxidant activity. Such results have been confirmed by basic in vitro studies. Moreover, phloretin-induced cell cycle arrest was associated with increased expression of p27 and decreased expression of cdk2, cdk4, cdk6, cyclin D, and cyclin E 53). Inhibition of intracellular signaling pathways as well as the PI3K/Akt/mTOR and ERK/Nrf2 signaling cascades was suppressed by phloretin in a dose-dependent manner 54). In addition, many previous studies have also proposed that phloretin triggered the mitochondrial apoptosis pathway 55), 56) and generated reactive oxygen species (ROS) 57). Most of these studies were accompanied by induction of cell growth arrest and apoptosis through upregulation of proapoptotic molecules such as Bax, Bak, and poly (ADP-ribose (adenosine diphosphate-ribose)) polymerase (cleaved) and downregulation of Bcl-2. The antioxidant agents N-acetyl-l-cysteine and glutathione weakened the effect of phloretin on glioblastoma cells. In conclusion, these results demonstrate that phloretin exerts a potent chemopreventive activity in human glioblastoma cells through the generation of ROS. Such effects may have some potential applications for clinical patients. For example, in acute hepatitis patients, liver damage is induced by several damaging factors, among which viral exposure, alcohol consumption, and drug and immune system issues are most popular 58). In addition to antioxidant effects, phloretin is also able to modulate inflammatory responses. A previous study demonstrated that phloretin suppressed the activation and function of mouse dendritic cells 59). The study results showed that phloretin disturbed the multiple intracellular signaling pathways in dendritic cells induced by the TLR4 agonist LPS, including ROS, mitogen-activated protein kinases (extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase), and NF-κB, thus reducing the production of inflammatory cytokines and chemokine 60).
4.Determination of Polyphenolic Profiles of Basque Cider Apple Varieties Using Accelerated Solvent Extraction. R. M. Alonso-Salces, E. Korta, A. Barranco, L. A. Berrueta, B. Gallo and F. Vicente, J. Agric. Food Chem., 2001, volume 49, pages 3761–3767.
5.Phloridzin: biosynthesis, distribution and physiological relevance in plants. Phytochemistry. 2010 Jun;71(8-9):838-43. doi: 10.1016/j.phytochem.2010.03.003. Epub 2010 Mar 29. https://www.ncbi.nlm.nih.gov/pubmed/20356611
7, 18.Hyson DA. A comprehensive review of apples and apple components and their relationship to human health. Adv Nutr 2011;2:408e20.
8.Jedrychowski W, Maugeri U, Popiela T, Kulig J, Sochacka-Tatara E, Pac A, Sowa A, Musial A. Case-control study on beneficial effect of regular consumption of apples on colorectal cancer risk in a population with relatively low intake of fruits and vegetables. Eur J Cancer Prev 2010;19:42e7.
9.Jaganathan SK, Vellayappan MV, Narasimhan G, Supriyanto E, Dewi DEO, Narayanan ALT, et al. Chemopreventive effect of apple and berry fruits against colon cancer. World J Gastroenterol 2014;20(45):17029e36.
10, 14, 36, 46.Yang KC, Tsai CY, Wang YJ, Wei PL, Lee CH, Chen JH, Wu CH, Ho YS. Apple polyphenol phloretin potentiates the anticancer actions of paclitaxel through induction of apoptosis in human hep G2 cells. Mol Carcinog 2009;48:420e31.
11, 13, 41.Wu CH, Ho YS, Tsai CY, Wang YJ, Tseng H, Wei PL, Lee CH, Liu RS, Lin SY. In vitro and in vivo study of phloretin-induced apoptosis in human liver cancer cells involving inhibition of type II glucose transporter. Int J Cancer 2009;124:2210e9.
12.Sudan S, Rupasinghe HP. Flavonoid-enriched apple fraction AF4 induces cell cycle arrest, DNA topoisomerase II inhibition, and apoptosis in human liver cancer HepG2 cells. Nutr Cancer 2014;66:1237e46.
15.Ramos S. Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention. J Nutr Biochem 2007;18:427e42.
16.Bouayed J, Hoffmann L, Bohn T. Total phenolics, flavonoids, anthocyanins and antioxidant activity following simulated gastro-intestinal digestion and dialysis of apple varieties: bioaccessibility and potential uptake. Food Chem 2011;128:14e21.
17.van der Sluis AA, Dekker M, Verkerk R, Jongen WM. An improved, rapid in vitro method to measure antioxidant activity. Application on selected flavonoids and apple juice. J Agric Food Chem 2000;48:4116e22.
19, 40.An apple a day to prevent cancer formation: Reducing cancer risk with flavonoids. Tu, Shih-Hsin et al. Journal of Food and Drug Analysis , Volume 25, Issue 1, 119-124.
20, 21, 22.Daily apple versus dried plum: impact on cardiovascular disease risk factors in postmenopausal women. Chai SC, Hooshmand S, Saadat RL, Payton ME, Brummel-Smith K, Arjmandi BH. J Acad Nutr Diet. 2012 Aug; 112(8):1158-68. https://jandonline.org/article/S2212-2672(12)00625-9/fulltext
23, 24, 25.Annurca (Malus pumila Miller cv. Annurca) apple as a functional food for the contribution to a healthy balance of plasma cholesterol levels: results of a randomized clinical trial. Tenore GC, Caruso D, Buonomo G, D’Urso E, D’Avino M, Campiglia P, Marinelli L, Novellino E. J Sci Food Agric. 2017 May; 97(7):2107-2115. https://onlinelibrary.wiley.com/doi/pdf/10.1002/jsfa.8016
26.Intake of whole apples or clear apple juice has contrasting effects on plasma lipids in healthy volunteers. Ravn-Haren G, Dragsted LO, Buch-Andersen T, Jensen EN, Jensen RI, Németh-Balogh M, Paulovicsová B, Bergström A, Wilcks A, Licht TR, Markowski J, Bügel S. Eur J Nutr. 2013 Dec; 52(8):1875-89.
27.Flavonoid-rich apples and nitrate-rich spinach augment nitric oxide status and improve endothelial function in healthy men and women: a randomized controlled trial. Bondonno CP, Yang X, Croft KD, Considine MJ, Ward NC, Rich L, Puddey IB, Swinny E, Mubarak A, Hodgson JM. Free Radic Biol Med. 2012 Jan 1; 52(1):95-102.
28.Bioavailability of epicatechin and effects on nitric oxide metabolites of an apple flavanol-rich extract supplemented beverage compared to a whole apple puree: a randomized, placebo-controlled, crossover trial. Hollands WJ, Hart DJ, Dainty JR, Hasselwander O, Tiihonen K, Wood R, Kroon PA. Mol Nutr Food Res. 2013 Jul; 57(7):1209-17.
29, 31.Fathy SM, Drees EA. Protective effects of Egyptian cloudy apple juice and apple peel extract on lipid peroxidation, antioxidant enzymes and inflammatory status in diabetic rat pancreas. BMC Complement Altern Med 2016;16:8.
30.Kim ES, Hong WK. An apple a day… does it really keep the doctor away? The current state of cancer chemoprevention. J Natl Cancer Inst 2005;97:468e70.
32.Yuan L, Meng L, Ma W, Xiao Z, Zhu X, Feng JF, Yu H, Xiao R. Impact of apple and grape juice consumption on the antioxidant status in healthy subjects. Int J Food Sci Nutr 2011;62:844e50.
33, 50.Ma L, Wang R, Nan Y, Li W, Wang Q, Jin F. Phloretin exhibits an anticancer effect and enhances the anticancer ability of cisplatin on non-small cell lung cancer cell lines by regulating expression of apoptotic pathways and matrix metalloproteinases. Int J Oncol 2016;48:843e53.
34, 51, 52.Xintaropoulou C, Ward C, Wise A, Marston H, Turnbull A, Langdon SP. A comparative analysis of inhibitors of the glycolysis pathway in breast and ovarian cancer cell line models. Oncotarget 2015;6:25677e95.
35.Park SY, Kim EJ, Shin HK, Kwon DY, Kim MS, Surh YJ, Park JH. Induction of apoptosis in HT-29 colon cancer cells by phloretin. J Med Food 2007;10:581e6.
37.Hong SM, Park CW, Kim SW, Nam YJ, Yu JH, Shin JH, Yun CH, Im SH, Kim KT, Sung YC, Choi KY. NAMPT suppresses glucose deprivation-induced oxidative stress by increasing NADPH levels in breast cancer. Oncogene 2016;35:3544e54.
38.Schiavano GF, De Santi M, Brandi G, Fanelli M, Bucchini A, Giamperi L, Giomaro G. Inhibition of breast cancer cell proliferation and in vitro tumorigenesis by a new red apple cultivar. PLoS One 2015;10:e0135840.
39.Qiao A, Wang Y, Xiang L, Wang C, He X. A novel triterpenoid isolated from apple functions as an anti-mammary tumor agent via a mitochondrial and caspase-independent apoptosis pathway. J Agric Food Chem 2015;63:185e91.
42, 43.Lin ST, Tu SH, Yang PS, Hsu SP, Lee WH, Ho CT, Wu CH, Lai YH, Chen MY, Chen LC. Apple polyphenol phloretin inhibits colorectal cancer cell growth via inhibition of the type 2 glucose transporter and activation of p53-mediated signaling. J Agric Food Chem 2016;64:6826e37.
44.Zhang D, Li YH, Mi M, Jiang FL, Yue ZG, Sun Y, Fan L, Meng J, Zhang X, Liu L, Mei QB. Modified apple polysaccharides suppress the migration and invasion of colorectal cancer cells induced by lipopolysaccharide. Nutr Res 2013;33:839e48.
45.Miura D, Miura Y, Yagasaki K. Effect of apple polyphenol extract on hepatoma proliferation and invasion in culture and on tumor growth, metastasis, and abnormal lipoprotein profiles in hepatoma-bearing rats. Biosci Biotechnol Biochem 2007;71:2743e50.
47.Devi MA, Das NP. In vitro effects of natural plant polyphenols on the proliferation of normal and abnormal human lymphocytes and their secretions of interleukin-2. Cancer Lett 1993;69:191e6.
48.Kobori M, Shinmoto H, Tsushida T, Shinohara K. Phloretininduced apoptosis in B16melanoma 4A5 cells by inhibition of glucosetransmembranetransport.Cancer Lett1997;119:207e12.
49, 53.Liu Y, Fan C, Pu L, Wei C, Jin H, Teng Y, Zhao M, Yu AC, Jiang F, Shu J, Li F, Peng Q, Kong J, Pan B, Zheng L, Huang Y. Phloretin induces cell cycle arrest and apoptosis of human glioblastoma cells through the generation of reactive oxygen species. J Neurooncol 2016;128:217e23.
54.Yang YC, Lii CK, Lin AH, Yeh YW, Yao HT, Li CC, Liu KL, Chen HW. Induction of glutathione synthesis and heme oxygenase 1 by the flavonoids butein and phloretin is mediated through the ERK/Nrf2 pathway and protects against oxidative stress. Free Radic Biol Med 2011;51:2073e81.
55.Vineetha VP, Soumya RS, Raghu KG. Phloretin ameliorates arsenic trioxide induced mitochondrial dysfunction in H9c2 cardiomyoblasts mediated via alterations in membrane permeability and ETC complexes. Eur J Pharmacol 2015;754:162e72.
56.Ullen A, Fauler G, Bernhart E, Nusshold C, Reicher H, Leis HJ, Malle E, Sattler W. Phloretin ameliorates 2-chlorohexadecanal-mediated brain microvascular endothelial cell dysfunction in vitro. Free Radic Biol Med 2012;53:1770e81.
57.Andrisse S, Koehler RM, Chen JE, Patel GD, Vallurupalli VR, Ratliff BA, Warren DE, Fisher JS. Role of GLUT1 in regulation of reactive oxygen species. Redox Biol 2014;2:764e71.
58.Zuo AR, Yu YY, Shu QL, Zheng LX, Wang XM, Peng SH, Xie YF, Cao SW. Hepatoprotective effects and antioxidant, antityrosinase activities of phloretin and phloretin isonicotinyl hydrazone. J Chin Med Assoc 2014;77:290e301.
59, 60.Lin CC, Chu CL, Ng CS, Lin CY, Chen DY, Pan IH, Huang KJ. Immunomodulation of phloretin by impairing dendritic cell activation and function. Food Funct 2014;5:997e1006.
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