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Fruit peel polyphenols demonstrate substantial anti-tumour effects in the model of breast cancer

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Abstract

Purpose

Fruit and vegetable intake is inversely correlated with cancer; thus, it is proposed that an extract of phytochemicals as present in whole fruits, vegetables, or grains may have anti-carcinogenic properties. Thus, the anti-tumour effects of fruit peel polyphenols (Flavin7) in the chemoprevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated.

Methods

Lyophilized substance of Flavin7 (F7) was administered at two concentrations of 0.3 and 3 % through diet. The experiment was terminated 14 weeks after carcinogen administration, and mammary tumours were removed and prepared for histopathological and immunohistochemical analysis. In addition, using an in vitro cytotoxicity assay, apoptosis and proliferation after F7 treatment in human breast adenocarcinoma (MCF-7) cells were performed.

Results

High-dose F7 suppressed tumour frequency by 58 % (P < 0.001), tumour incidence by 24 % (P < 0.05), and lengthened latency by 8 days (P > 0.05) in comparison with the control rats, whereas lower dose of F7 was less effective. Histopathological analysis of tumours showed significant decrease in the ratio of high-/low-grade carcinomas after high-dose F7 treatment. Immunohistochemical analysis of rat carcinoma cells in vivo found a significant increase in caspase-3 expression and significant decrease in Bcl-2, Ki67, and VEGFR-2 expression in the high-dose group. Both doses demonstrated significant positive effects on plasma lipid metabolism in rats. F7 significantly decreased survival of MCF-7 cells in vitro in MTT assay by dose- and time-dependent manner compared to control. F7 prevented cell cycle progression by significant enrichment in G1 cell populations. Incubation with F7 showed significant increase in the percentage of annexin V-/PI-positive MCF-7 cells and DNA fragmentation.

Conclusions

Our results reveal a substantial tumour-suppressive effect of F7 in the breast cancer model. We propose that the effects of phytochemicals present in this fruit extract are responsible for observed potent anti-cancer activities.

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Abbreviations

BrdU:

5-Bromo-20-deoxyuridine

FCM:

Flow cytometry analysis

FLAV 0.3/FLAV 3:

Experimental group with dietary-administered Flavin7 in a concentration of 0.3 and 3 %

F7:

Flavin7

HG:

High grade

LDL:

Low-density lipoprotein

LG:

Low grade

MCF-7:

Human adenocarcinoma cell lines, oestrogen receptor-positive

MDA-MB-231:

Human breast adenocarcinoma cell line, oestrogen receptor-negative

NMU:

N-methyl-N-nitrosourea

p.o.:

Per os

VEGF:

Vascular endothelial growth factor

VEGFR-2:

Vascular endothelial growth factor receptor-2

VLDL:

Very low-density lipoprotein

References

  1. Yochum L, Kushi LH, Meyer K, Folsom AR (1999) Dietary flavonoid intake and risk of cardiovascular disease in postmenopausal women. Am J Epidemiol 149:943–949

    Article  CAS  Google Scholar 

  2. Willett WC (1994) Micronutrients and cancer risk. Am J Clin Nutr 59:1162S–1165S

    CAS  Google Scholar 

  3. Hu FB, Willett WC (2002) Optimal diets for prevention of coronary heart disease. JAMA 288:2569–2578

    Article  CAS  Google Scholar 

  4. Yiannakopoulou ECH (2014) Effect of green tea catechins on breast carcinogenesis: a systematic review of in vitro and in vivo experimental studies. Eur J Cancer Prev 3:84–89

    Article  Google Scholar 

  5. Cutler GJ, Nettleton JA, Ross JA, Harnack LJ, Jacobs DR Jr, Scrafford CG et al (2008) Dietary flavonoid intake and risk of cancer in postmenopausal women: the Iowa Women’s Health Study. Int J Cancer 23:664–671

    Article  Google Scholar 

  6. Fink N, Steck SE, Wolff MS, Britton JA, Kabat GC, Gaudet MM et al (2007) Dietary flavonoid intake and breast cancer survival among women on Long Island. Cancer Epidemiol Biomarkers Prev 16:2285–2292

    Article  CAS  Google Scholar 

  7. Neuhouser ML (2004) Dietary flavonoids and cancer risk: evidence from human population studies. Nutr Cancer 50:1–7

    Article  CAS  Google Scholar 

  8. Sun M, Nie S, Pan X, Zhang R, Fan Z, Wang S (2014) Quercetin-nanostructured lipid carriers: characteristics and anti-breast cancer activities in vitro. Collid Surf B 113:15–24

    Article  CAS  Google Scholar 

  9. Purushothaman A, Nandhakumar E, Sachdanandam P (2013) Phytochemical analysis and anticancer capacity of Shemamruthaa, a herbal formulation against DMBA- induced mammary carcinoma in rats. Asian Pac J Trop Med 6:925–933

    Article  CAS  Google Scholar 

  10. Roy S, Banerjee B, Vedasiromoni JR (2014) Cytotoxic and apoptogenic effect of Swietenia mahagoni (L.) Jacq. leaf extract in human leukemic cell lines U937, K562 and HL-60. Environ Toxicol Pharmacol 37:234–247

    Article  CAS  Google Scholar 

  11. Li Y, Duan S, Jia H, Bai C, Zhang L, Wang Z (2014) Flavonoids from tartary buckwheat induce G2/M cell cycle arrest and apoptosis in human hepatoma HepG2 cells. Acta Biochim Biophys Sin (Shanghai) 46:460–470

    Article  CAS  Google Scholar 

  12. Zhang Y, Li Q, Ge Y, Chen Y, Chen J, Dong Y, Shi W (2013) Silibinin triggers apoptosis and cell-cycle arrest of SGC7901 cells. Phytother Res 27:397–403

    Article  CAS  Google Scholar 

  13. Russo J, Russo IH (2000) Atlas and histologic classification of tumors of the rat mammary gland. J Mammary Gland Biol Neoplasia 5:187–200

    Article  CAS  Google Scholar 

  14. Murín R, Drgová A, Kaplán P, Dobrota D, Lehotský J (2001) Ischemia/Reperfusion-induced oxidative stress causes structural changes of brain membrane proteins and lipids. Gen Physiol Biophys 20:431–438

    Google Scholar 

  15. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  CAS  Google Scholar 

  16. Kisková T, Jendželovský R, Rentsen E, Maier-Salamon A, Kokošová N, Papčová Z et al (2014) Resveratrol enhances the chemopreventive effect of celecoxib in chemically induced breast cancer in rats. Eur J Cancer Prev 23:506–513

    Article  Google Scholar 

  17. Kisková T, Ekmekcioglu C, Garajová M, Orendáš P, Bojková B, Bobrov N et al (2012) A combination of resveratrol and melatonin exerts chemopreventive effects in N-methyl-N-nitrosourea-induced rat mammary carcinogenesis. Eur J Cancer Prev 21:163–170

    Article  Google Scholar 

  18. Bilotto S, Spagnuolo C, Russo M, Tedesco I, Laratta B, Russo GL (2013) Dietary phytochemicals in chemoprevention of cancer: an update. IEMAMC 13:2–24

    Article  CAS  Google Scholar 

  19. Russo GL (2007) Ins and outs of dietary phytochemicals in cancer chemoprevention. Biochem Pharmacol 74:533–544

    Article  CAS  Google Scholar 

  20. Ziegler CC, Rainwater L, Whelan J, McEntee MF (2004) Dietary resveratrol does not affect intestinal tumorigenesis in Apc(Min/+) mice. J Nutr 134:5–10

    CAS  Google Scholar 

  21. Kubatka P, Kapinová A, Kružliak P, Kello M, Výbohová D, Kajo K, Novák M, Chripková M, Adamkov M, Péč M, Mojžiš J, Bojková B, Kassayová M, Stollárová N, Dobrota D (2015) Antineoplastic effects of Chlorella pyrenoidosa in the breast cancer model. Nutrition 31:560–569

    Article  CAS  Google Scholar 

  22. Zhang J, Park HS, Kim JA, Hong GE, Nagappan A, Park KI, Kim GS (2014) Flavonoids identified from korean Scutellaria baicalensis induce apoptosis by ROS generation and caspase activation on human fibrosarcoma cells. Am J Chin Med 42:465–483

    Article  CAS  Google Scholar 

  23. Sudan S, Rupasinghe HP (2014) Flavonoid-enriched apple fraction AF4 induces cell cycle arrest, DNA topoisomerase II inhibition, and apoptosis in human liver cancer HepG2 cells. Nutr Cancer 66:1237–1246

    Article  CAS  Google Scholar 

  24. Oh SB, Hwang C, Song SY, Jung YY, Yun HM, Sok C et al (2014) Anti-cancer effect of tectochrysin in NSCLC cells through overexpression of death receptor and inactivation of STAT3. Cancer Lett 353:95–103

    Article  CAS  Google Scholar 

  25. Kim JA, Kim DH, Hossain MA, Kim MY, Sung B, Yoon JH et al (2014) HS-1793, a resveratrol analogue, induces cell cycle arrest and apoptotic cell death in human breast cancer cells. Int J Oncol 44:473–480

    CAS  Google Scholar 

  26. Chen ZT, Tao ZZ, Chen SM, Chen C, Li F, Xiao BK (2013) Indole-3-carbinol inhibits nasopharyngeal carcinoma growth through cell cycle arrest in vivo and in vitro. PLoS One 8:e82288

    Article  Google Scholar 

  27. Cserni G, Voeroes A, Liepniece-Karele I, Bianchi S, Vezzosi V, Grabau D et al (2014) Distribution pattern of the Ki67 labelling index in breast cancer and its implications for choosing cut-off values. Breast 23:259–263

    Article  Google Scholar 

  28. Wang Z, Wang N, Han S, Wang D, Mo S, Yu L et al (2013) Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway. PLoS One 8:e68566

    Article  CAS  Google Scholar 

  29. Lirdprapamongkol K, Sakurai H, Abdelhamed S, Yokoyama S, Maruyama T, Athikomkulchai S et al (2013) A flavonoid chrysin suppresses hypoxic survival and metastatic growth of mouse breast cancer cells. Oncol Rep 30:2357–2364

    CAS  Google Scholar 

  30. Mojžiš J, Šarisský M, Pilátová M, Voharová V, Varinská L, Mojzisová G et al (2008) In vitro antiproliferative and antiangiogenic effects of Flavin7. Physiol Res 57:413–420

    Google Scholar 

  31. Hussain SP, Lorne J, Harris CC (2003) Radical causes of cancer. Nat Rev Cancer 3:276–284

    Article  CAS  Google Scholar 

  32. Malencik DA, Anderson SR (2003) Dityrosine as a product of oxidative stress and fluorescent probe. Amino Acids 25:233–247

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Scientific Grant Agency of the Ministry of Education of the Slovak Republic under the Contract No. VEGA 1/0071/13, VEGA 1/0043/12 and by the Slovak Research and Development Agency under the Contract No. APVV-0325-07. This work was supported by the Grant “Martin Biomedical Centre” (ITMS: 26220220187), “Competence center for research and development in diagnosis and therapy”, code: 26220220153, and the Grant FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123), both projects co-funded from EU sources and European Regional Development Fund. This study was also supported by the project Medicínsky univerzitný park v Košiciach (MediPark, Košice) ITMS:26220220185 supported by Operational Programme Research and Development (OP VaV-2012/2.2/08-RO) (Contract No. OPVaV/12/2013). We thank to Eva Jakubovičová for technical support.

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University, Malá Hora 4, 036 01, Martin, Slovakia

    Peter Kubatka & Martin Péč

  2. Department of Medical Biochemistry, Comenius University, Martin, Slovakia

    Andrea Kapinová, Silvia Mahmood, Radovan Murin & Dušan Dobrota

  3. Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Tr. SNP 1, 040 01, Kosice, Slovakia

    Martin Kello, Tischlerová Viera & Ján Mojžiš

  4. International Clinical Research Center, St. Anne’s University Hospital, Masaryk University, Pekarska 53, 656 91, Brno, Czech Republic

    Peter Kruzliak

  5. Department of Pathology, St. Elisabeth Oncology Institute, Slovak Medical University, Heydukova 10, 812 50, Bratislava, Slovakia

    Karol Kajo

  6. Department of Anatomy, Comenius University, Martin, Slovakia

    Desanka Výbohová

  7. The Centre for Chronic Disease Prevention and Management (CCDPM), Western CHRE, Victoria University, St Albans, Australia

    Anthony Zulli

  8. Department of Histology and Embryology, Comenius University, Martin, Slovakia

    Marián Adamkov

  9. Department of Animal Physiology, Institute of Biological and Ecological Sciences, Faculty of Science, P. J. Šafárik University, Moyzesova 11, 040 01, Kosice, Slovakia

    Monika Kassayová & Bianka Bojková

  10. Department of Biology and Ecology, Faculty of Education, Catholic University in Ružomberok, Hrabovská cesta 1, 034 01, Ružomberok, Slovakia

    Nadežda Stollárová

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  1. Peter Kubatka
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  2. Andrea Kapinová
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Correspondence to Peter Kubatka or Martin Péč.

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Kubatka, P., Kapinová, A., Kello, M. et al. Fruit peel polyphenols demonstrate substantial anti-tumour effects in the model of breast cancer. Eur J Nutr 55, 955–965 (2016). https://doi.org/10.1007/s00394-015-0910-5

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  • DOI: https://doi.org/10.1007/s00394-015-0910-5

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