Biological Trace Element Research

, Volume 187, Issue 1, pp 80–91 | Cite as

Selenium Nanoparticles Induce the Chemo-Sensitivity of Fluorouracil Nanoparticles in Breast and Colon Cancer Cells

  • Ahmed A. Abd-Rabou
  • Aziza B. Shalby
  • Hanaa H. AhmedEmail author


Drug resistance is a major challenge of breast and colon cancer therapies leading to treatment failure. The main objective of the current study is to investigate whether selenium nanoparticles (nano-Se) can induce the chemo-sensitivity of 5-fluorouracil (FU)-encapsulated poly (D, L-lactide-co-glycolide) nanoparticles (nano-FU) in breast and colon cancer cell lines. Nano-Se and nano-FU were synthesized and characterized, then applied individually or in combination upon MCF7, MDA-MB-231, HCT 116, and Caco-2 cancerous cell lines. Cytotoxicity, cellular glucose uptake, and apoptosis, as well as malondialdehyde (MDA), nitric oxide (NO), and zinc (Zn) levels, were investigated upon the different treatments. We have resulted that nano-FU induced cell death in MCF7 and Caco-2 more effectively than MDA-MB-231 and HCT 116 cell lines. Moreover, nano-FU plus nano-Se potentiate MCF7 and Caco-2 chemo-sensitivity were higher than MDA-MB-231 and HCT 116 cancerous cell lines. It is relevant to note that Se and FU nano-formulations inhibited cancer cell bioenergetics via glucose uptake slight blockage. Furthermore, nano-FU increased the levels of NO and MDA in media over cancer cells, while their combinations with nano-Se rebalance the redox status with Zn increment. We noticed that MCF7 cell line is sensitive, while MDA-MB-231 cell line is resistant to Se and nano-Se. This novel approach could be of great potential to enhance the chemo-sensitivity in breast and colon cancer cells.


Se nanoparticles FU nanoparticles Cancer resistance 


Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflict of interests.


  1. 1.
    Kotepui M (2016) Diet and risk of breast cancer. Contemp Oncol (Pozn) 20:13–19. CrossRefGoogle Scholar
  2. 2.
    Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Afzal S, Jensen SA, Vainer B, Vogel U, Matsen JP, Sorensen JB, Andersen PK, Poulsen HE (2009) MTHFR polymorphisms and 5-FU-based adjuvant chemotherapy in colorectal cancer. Ann Oncol 20:1660–1666. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Canman CE, Tang HY, Normolle DP, Lawrence TS, Maybaum J (1992) Variations in patterns of DNA damage induced in human colorectal tumor cells by 5-fluorodeoxyuridine: implications for mechanisms of resistance and cytotoxicity. Proc Natl Acad Sci U S A 89:10474–10478 Scholar
  5. 5.
    de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Boige V, Mendiboure J, Pignon JP, Loriot MA, Castaing M, Barrois M, Malka D, Tregouet DA, Bouche O, Le Corre D, Miran I, Mulot C, Ducreux M, Beaune P, Laurent-Puig P (2010) Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000–05. J Clin Oncol 28:2556–2564. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Abd-Rabou AA, Bharali DJ, Mousa SA (2018) Taribavirin and 5-Flurouracil-loaded Pegylated-lipid nanoparticle synthesis, p38 docking, and Antiproliferative effects on MCF-7 breast Cancer. Pharm Res (In Press) 35:76. CrossRefGoogle Scholar
  8. 8.
    Xue X, Liang XJ (2012) Overcoming drug efflux-based multidrug resistance in cancer with nanotechnology. Chin J Cancer 31:100–109. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Dixon JM (2014) Endocrine resistance in breast Cancer. New J Sci 2014:1–27. CrossRefGoogle Scholar
  10. 10.
    Huang CY, Yu LCH (2015) Pathophysiological mechanisms of death resistance in colorectal carcinoma. World J Gastroenterol 21:11777–11792. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Księżakowska-Łakoma K, Żyła M, Wilczyński JR (2014) Mitochondrial dysfunction in cancer. PrzMenopauzalny 13:136–144. CrossRefGoogle Scholar
  12. 12.
    Zhong W, Oberley TD (2001) Redox-mediated effects of selenium on apoptosis and cell cycle in the LNCaP human prostate cancer cell line. Cancer Res 61:7071–7078 PubMedPubMedCentralGoogle Scholar
  13. 13.
    Schrauzer GN (2009) Selenium and selenium-antagonistic elements in nutritional cancer prevention. Crit Rev Biotechnol 29:10–17. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Luo H, Yang Y, Huang F, Li F, Jiang Q, Shi K, Xu C (2012) Selenite induces apoptosis in colorectal cancer cells via AKT-mediated inhibition of β-catenin survival axis. Cancer Lett 315:78–85. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Fernandes AP, Gandin V (2015) Selenium compounds as therapeutic agents in cancer. Biochim Biophys Acta 1850:1642–1660. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sanmartín C, Plano D, Sharma AK, Palop JA (2012) Selenium compounds, apoptosis and other types of cell death: an overview for cancer therapy. Int J Mol Sci 13:9649–9672. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gupta S, Jaworska-Bieniek K, Lubinski J, Jakubowska A (2013) Can selenium be a modifier of cancer risk in CHEK2 mutation carriers? Mutagenesis 28:625–629. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Zhang J, Wang H, Bao Y, Zhang L (2004) Nano red elemental selenium has no size effect in the induction of seleno-enzymes in both cultured cells and mice. Life Sci 75:237–244. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Gulyas G, Csosz E, Prokisch J, Javor A, Mezes M, Erdelyi M, Balogh K, Janaky T, Szabo Z, Simon A, Czegledi L (2016) Effect of nano-sized, elemental selenium supplement on the proteome of chicken liver. J Anim Physiol Anim Nutr (Berl) 101:502–510. CrossRefGoogle Scholar
  20. 20.
    Yu B, Li X, Zheng W, Feng Y, Wong YS, Chen T (2014) pH-responsive cancer-targeted selenium nanoparticles: a transformable drug carrier with enhanced theranostic effects. J Mater Chem B 2:5409–5418. CrossRefGoogle Scholar
  21. 21.
    Zheng S, Li X, Zhang Y, Xie Q, Wong YS, Zheng W, Chen T (2012) PEG-nanolized ultrasmall selenium nanoparticles overcome drug resistance in hepatocellular carcinoma HepG2 cells through induction of mitochondria dysfunction. Int J Nanomedicine 7:3939–3949. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Abd-Rabou AA, Ahmed HH (2017) CS-PEG decorated PLGA nano-prototype for delivery of bioactive compounds: a novel approach for induction of apoptosis in HepG2 cell line. Advances in medical sciences. Adv Med Sci 62:357–367. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Shalby AB, Abd-Rabou AA, Ahmed HH (2017) Nano-se crosstalks with nano-DOX/FU to selectively hack hepatic cancer cells and spare normal cells healthy: a mechanism-based study. J Appl Pharm Sci 7(8):003–012. CrossRefGoogle Scholar
  24. 24.
    Zhang JS, Gao XY, Zhang LD, Bao YP (2001) Biological effects of a nano red elemental selenium. Biofactors 15:27–38 CrossRefGoogle Scholar
  25. 25.
    Parveen S, Sahoo SK (2011) Long circulating chitosan/PEG blended PLGA nanoparticle for tumor drug delivery. Eur J Pharmacol 670:372–383. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    van Meerloo J, Kaspers GJ, Cloos J (2011) Cell sensitivity assays: the MTT assay. Methods Mol Biol 731:237–245. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Brigelius-Floh’e R, Lötzer K, Maurer S, Schultz M, Leist M (1996) Utilization of selenium from different chemical entities for selenoproteinbiosymthesis by mammalian cell lines. Biofactors 5:125–131,%20BioFactors[all]&cmd=correctspelling Google Scholar
  28. 28.
    Combs GF, Garbisu C, Yee BC, Yee A, Carlson DE, Smith NR, Magyarosy AC, Leighton T, Buchanan BB (1996) Bioavailability of selenium accumulated by selenite-reducing bacteria. Biol Trace Elem Res 52:209–225. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ghadi FE, Ghara AR, Bhattacharyya S, Dhawan DK (2009) Selenium as a chemopreventive agent in experimentally induced colon carcinogenesis. World J Gastrointest Oncol 1:74–81. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Abd-Rabou AA, Assirey EA, Saad R, Ibrahim HS (2018) Metallocenes-induced apoptosis in human hepatic cancer HepG2 cells: the prodigy of zamzam water. Int J Pharmacol 14:260–270CrossRefGoogle Scholar
  31. 31.
    Dong Y, Ganther HE, Stewart C, Ip C (2002) Identification of molecular targets associated with selenium-induced growth inhibition in human breast cells using cDNA microarrays. Cancer Res 62:708–714 PubMedPubMedCentralGoogle Scholar
  32. 32.
    Sanmartín C, Plano D, Palop JA (2008) Selenium compounds and apoptotic modulation: a new perspective in cancer therapy. Mini Rev Med Chem 8:1020–1031 CrossRefGoogle Scholar
  33. 33.
    Ahmed HH, Khalil WK, Hamza AH (2014) Molecular mechanisms of Nano-selenium in mitigating hepatocellular carcinoma induced by N-nitrosodiethylamine (NDEA) in rats. Toxicol Mech Methods 24:593–602. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ruseva B, Atanasova M, Tsvetkova R, Betova T, Mollova M, Alexandrova M, Laleva P, Dimitrova A (2015) Effect of Selenium Supplementation on Redox Status of the Aortic Wall in Young Spontaneously Hypertensive Rats. Effect of Selenium Supplementation on Redox Status of the Aortic Wall in Young Spontaneously Hypertensive Rats Oxid Med Cell Longev 2015:609053–609010. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Yeo JK, Cha SD, Cho CH, Kim SP, Cho JW, Baek WK, Suh MH, Kwon TK, Park JW, Suh SI (2002) Se-methylselenocysteine induces apoptosis through caspase activation and Bax cleavage mediated by calpain in SKOV-3 ovarian cancer cells. Cancer Lett 182:83–92 CrossRefGoogle Scholar
  36. 36.
    Christensen MJ, Nartey ET, Hada AL, Legg RL, Barzee BR (2007) High selenium reduces NF-kappaB-regulated gene expression in uninduced human prostate cancer cells. Nutr Cancer 58:197–204. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Nadiminty N, Gao AC (2008) Mechanisms of selenium chemoprevention and therapy in prostate cancer. Mol Nutr Food Res 52:1247–1260. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Saifo MS, Rempinski DR Jr, Rustum YM, Azrak RG (2010) Targeting the oncogenic protein beta-catenin to enhance chemotherapy outcome against solid human cancers. Mol Cancer 9:310. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Favaro E, Bensaad K, Chong MG, Tennant DA, Ferguson DJ, Snell C, Steers G, Turley H, Li JL, Gunther UL, Buffa FM, McIntyre A, Harris AL (2012) Glucose utilization via glycogen phosphorylase sustains proliferation and prevents premature senescence in cancer cells. Cell Metab 16:751–764. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Jackson MI, Jr CGF (2008) Selenium and anticarcinogenesis: underlying mechanisms. Curr Opin Clin Nutr Metab Care 11:718–726. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Xiao H, Jiang Y, Qi Y, Zhou X, Gong C, Huang C, Li M (2012) Effects of selenium and zinc on the proliferation of human esophageal cancer cell line studied by serophysiology. Wei Sheng Yan Jiu 41:185–190 PubMedPubMedCentralGoogle Scholar
  42. 42.
    Yu RA, Xia T, Wang AG, Chen XM (2006) Effects of selenium and zinc on renal oxidative stress and apoptosis induced by fluoride in rats. Biomed Environ Sci 19(6):439–444 PubMedPubMedCentralGoogle Scholar
  43. 43.
    Lunyin Y, Dong X, Hanqiao L (1996) Influence of zinc, managenese and selenium on superoxide dismutase activity in lung cancer tissue and cell in culture. Chin J Cancer Res 8(1):42–45CrossRefGoogle Scholar
  44. 44.
    Liu T, Zeng L, Jiang W, Fu Y, Zheng W, Chen T (2015) Rational design of cancer-targeted selenium nanoparticles to antagonize multidrug resistance in cancer cells. Nanomedicine 11:947–958. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Jia X, Liu Q, Zou S, Xu X, Zhang L (2015) Construction of selenium nanoparticles/β-glucan composites for enhancement of the antitumor activity. Carbohydr Polym 117:434–442. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ahmed A. Abd-Rabou
    • 1
  • Aziza B. Shalby
    • 1
  • Hanaa H. Ahmed
    • 1
    Email author
  1. 1.Hormones Department, Medical Research DivisionNational Research CentreGizaEgypt

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