Food Biophysics

, Volume 14, Issue 1, pp 80–89 | Cite as

Caffeic Acid Phenethyl Ester Loaded in Microemulsions: Enhanced In Vitro Activity against Colon and Breast Cancer Cells and Possible Cellular Mechanisms

  • Huaiqiong Chen
  • Yongguang Guan
  • Seung Joon Baek
  • Qixin ZhongEmail author


Caffeic acid phenethyl ester (CAPE) has high cytotoxicity against various cancer cells but has low water solubility and poor bioavailability. The objective of this work was to study a fully-dilutable oil-in-water microemulsion as a delivery vehicle of CAPE and the impacts on cellular uptake and expression of relevant proteins. Up to 3.30% w/w CAPE was dissolved in the microemulsion with droplets smaller than 20 nm and stable in 180 days. CAPE in the microemulsion had the significantly increased anti-proliferative activity against human HCT-116 colorectal and MCF-7 breast cancer cells than that in dimethyl sulfoxide. Dissolving CAPE in the microemulsion enhanced the cellular uptake according to fluorescence microscopy, flow cytometry, and HPLC. Subsequently, cyclin D1 was suppressed and p53 was induced, which regulated cell cycle and apoptosis, respectively, thereby enhancing anti-cancer activity. Findings from the present work suggest the potential of the studied microemulsion as a vehicle of CAPE for development of cancer intervention strategies.


Microemulsion Caffeic acid phenethyl ester Colon cancer Breast cancer Cellular uptake Protein expression 



The authors would like to thank Dianne Jean Trent for the technical assistance in flow cytometry and Dr. Gabriel Silva for providing training and technical assistance on western blotting analysis. This work was supported by the University of Tennessee Institute of Agriculture and the USDA NIFA Hatch Project 223984. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the U.S. Department of Agriculture.

Compliance with Ethical Standards

Conflict of Interest

The authors declare no competing financial interest.


  1. 1.
    S. A. Huang, C. P. Zhang, K. Wang, G. Q. Li, and F. L. Hu, Molecules 19, 19610 (2014), 12, 19632Google Scholar
  2. 2.
    Y.J. Chen, M.S. Shiao, S.Y. Wang, Anti-Cancer Drug 12(2), 143–149 (2001)Google Scholar
  3. 3.
    Y.J. He, B.H. Liu, D.B. Xiang, Z.Y. Qiao, T. Fu, Y.H. He, World J Gastroentero 12(31), 4981–4985 (2006)Google Scholar
  4. 4.
    J. Wu, C. Omene, J. Karkoszka, M. Bosland, J. Eckard, C.B. Klein, K. Frenkel, Cancer Lett. 308(1), 43–53 (2011)Google Scholar
  5. 5.
    S. Gao, M. Hu, Mini-Rev. Med. Chem. 10(6), 550–567 (2010)Google Scholar
  6. 6.
    H.Y. Lee, Y.I. Jeong, E.J. Kim, K.D. Lee, S.H. Choi, Y.J. Kim, D.H. Kim, K.C. Choi, J Pharm Sci-Us 104(1), 144–154 (2015)Google Scholar
  7. 7.
    E. Gundogdu, I.G. Alvarez, E. Karasulu, Int. J. Nanomedicine 6, 631 (2011)Google Scholar
  8. 8.
    F. Dehghani, N. Farhadian, S. Golmohammadzadeh, A. Biriaee, M. Ebrahimi, M. Karimi, Eur. J. Pharm. Sci. 96, 479–489 (2017)Google Scholar
  9. 9.
    M.H. Alkhatib, S.S. Al-Merabi, J Drug Deliv Sci Tec 24(4), 373–379 (2014)Google Scholar
  10. 10.
    M. Kotmakchiev, V.B. Cetintas, G. Kantarci, Curr Opin Biotech 22, S127–S128 (2011)Google Scholar
  11. 11.
    C. Raffaella, L. Casettari, L. Fagioli, M. Cespi, G. Bonacucina, W. Baffone, Int. J. Food Microbiol. 241, 132 (2017)Google Scholar
  12. 12.
    K. Tong, C.H. Zhao, D.J. Sun, Colloid Surface A 497, 101–108 (2016)Google Scholar
  13. 13.
    Z.B. Xu, J. Jin, M.Y. Zheng, Y. Zheng, X.B. Xu, Y.F. Liu, X.G. Wang, Food Chem. 204, 194–200 (2016)Google Scholar
  14. 14.
    Q.M. Ma, Q.X. Zhong, Food Res. Int. 71, 118–125 (2015)Google Scholar
  15. 15.
    H. Chen, Y. Guan, Q. Zhong, J. Agric. Food Chem. 63(3), 983–989 (2015)Google Scholar
  16. 16.
    H. Chen, Q. Zhong, Food Chem. 174, 630–636 (2015)Google Scholar
  17. 17.
    K. Pan, Y. Luo, Y. Gan, S.J. Baek, Q. Zhong, Soft Matter 10(35), 6820–6830 (2014)Google Scholar
  18. 18.
    M. H. Penner, in Food Analysis, edited by S. Nielsen (Springer, 2017), pp. 89Google Scholar
  19. 19.
    D. Qu, Y. Ma, W. Sun, Y. Chen, J. Zhou, C. Liu, M. Huang, Int. J. Nanomedicine 10, 1173 (2015)Google Scholar
  20. 20.
    M.H. Al-Douh, H.B. Sahib, H. Osman, S. Abd Hamid, S.M. Salhimi, Asian Pac J Cancer P 13(8), 4075–4079 (2012)Google Scholar
  21. 21.
    A. Jedinak, D. Sliva, Int. J. Oncol. 33, 1307 (2008)Google Scholar
  22. 22.
    P.M.R. Pereira, N. Berisha, N.V.S.D.K. Bhupathiraju, R. Fernandes, J.P.C. Tome, C.M. Drain, PLoS One 12(5), e0177737 (2017)Google Scholar
  23. 23.
    M.L. Bondi et al., J. Agric. Food Chem. 65(7), 1342–1352 (2017)Google Scholar
  24. 24.
    Y. Ting, Y.-S. Chiou, M.-H. Pan, C.-T. Ho, Q. Huang, J. Funct. Food 15, 264–273 (2015)Google Scholar
  25. 25.
    R. Guo, X. Fu, J. Chen, L. Zhou, G. Chen, J. Agric. Food Chem. 64(32), 6286–6294 (2016)Google Scholar
  26. 26.
    P. Sukamporn, P. Rojanapanthu, G. Silva, X.B. Zhang, W. Gritsanapan, S.J. Baek, Life Sci. 152, 60–66 (2016)Google Scholar
  27. 27.
    T. Wang, R. Wang, Z. Chen, and Q. Zhong, RSC Adv. 7, 43455 (2017), 69, 43463Google Scholar
  28. 28.
    T. Wang, H. Chen, R. Wang, Z. Chen, and Q. Zhong, RSC Adv. 7, 49953 (2017), 79, 49961Google Scholar
  29. 29.
    L.A. Fiel, R.V. Contri, J.F. Bica, F. Figueiro, A.M.O. Battastini, S.S. Guterres, A.R. Pohlmann, Nanoscale Res. Lett. 9(1), 233 (2014)Google Scholar
  30. 30.
    T. Sarkar, S. Banerjee, S. Mukherjee, A. Hussain, Dalton T 45(15), 6424–6438 (2016)Google Scholar
  31. 31.
    I. Hafner-Bratkovič, J. Gašperšič, L.M. Šmid, M. Bresjanac, R. Jerala, J. Neurochem. 104(6), 1553–1564 (2008)Google Scholar
  32. 32.
    C.J.D. Osterman, J.C. Lynch, P. Leaf, A. Gonda, H.R.F. Bennit, D. Griffiths, N.R. Wall, PLoS One 10(7), e0132845 (2015)Google Scholar
  33. 33.
    S. Banerjee, A.K. Sahoo, A. Chattopadhyay, S.S. Ghosh, Nanotechnology 25(34), 345102 (2014)Google Scholar
  34. 34.
    D. Wang, D.B. Xiang, Y.J. He, Z.P. Li, X.H. Wu, J.H. Mou, H.L. Xiao, Q.H. Zhang, World J Gastroentero 11(26), 4008–4012 (2005)Google Scholar
  35. 35.
    G. Murtaza, A. Sajjad, Z. Mehmood, S.H. Shah, A.R. Siddiqi, J. Food Drug Anal. 23(1), 11–18 (2015)Google Scholar
  36. 36.
    K. Kettler, K. Veltman, D. van de Meent, A. van Wezel, A.J. Hendriks, Env. Toxicol. Chem. 33(3), 481–492 (2014)Google Scholar
  37. 37.
    M. Sun, S.F. Nie, X. Pan, R.W. Zhang, Z.Y. Fan, S. Wang, Colloid Surface B 113, 15–24 (2014)Google Scholar
  38. 38.
    D. Qu, H.J. Lin, N. Zhang, J.W. Xue, C. Zhang, Carbohyd Polym 92(1), 545–554 (2013)Google Scholar
  39. 39.
    Y. Fang, Z.P. Cao, Q. Hou, C. Ma, C.S. Yao, J.X. Li, X.R. Wu, C.S. Huang, Mol. Cancer Ther. 12(8), 1492–1503 (2013)Google Scholar
  40. 40.
    M.F. Fu, C.G. Wang, Z.P. Li, T. Sakamaki, R.G. Pestell, Endocrinology 145(12), 5439–5447 (2004)Google Scholar
  41. 41.
    E.A. Musgrove, C.E. Caldon, J. Barraclough, A. Stone, R.L. Sutherland, Nat. Rev. Cancer 11(8), 558–572 (2011)Google Scholar
  42. 42.
    Z. Wang, Y. Sun, Transl. Oncol. 3(1), 1–12 (2010)Google Scholar
  43. 43.
    Y. Pan, R.V. Tikekar, N. Nitin, Int. J. Pharm. 450(1-2), 129–137 (2013)Google Scholar
  44. 44.
    N. Gautam, A.K. Mantha, S. Mittal, BioMed res. Int. 2014 (2014)Google Scholar
  45. 45.
    A.L. Cao, Q.F. Tang, W.C. Zhou, Y.Y. Qiu, S.J. Hu, P.H. Yin, J. Asian Nat. Prod. Res. 17(1), 56–63 (2015)Google Scholar
  46. 46.
    A. Kato et al., Oncotarget 6, 42963 (2015)Google Scholar
  47. 47.
    S.H. Lee, M. Cekanova, S.J. Baek, Mol. Carcinogen 47(3), 197–208 (2008)Google Scholar
  48. 48.
    X. Zhang, K.W. Min, J. Wimalasena, S.J. Baek, J. Cancer Res. Clinical Oncol. 138(12), 2051–2060 (2012)Google Scholar
  49. 49.
    E.P.I. Chiang, S.Y. Tsai, Y.H. Kuo, M.H. Pai, H.L. Chiu, R.L. Rodriguez, F.Y. Tang, PLoS One 9(6), e99631 (2014)Google Scholar
  50. 50.
    H.P. Lin, S.S. Jiang, C.P. Chuu, PLoS One 7(2), e31286 (2012)Google Scholar

Copyright information

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

Authors and Affiliations

  • Huaiqiong Chen
    • 1
  • Yongguang Guan
    • 1
  • Seung Joon Baek
    • 2
    • 3
  • Qixin Zhong
    • 1
    Email author
  1. 1.Department of Food ScienceThe University of TennesseeKnoxvilleUSA
  2. 2.Department of Biomedical and Diagnostic SciencesThe University of TennesseeKnoxvilleUSA
  3. 3.College of Veterinary Medicine and Research Institute for Veterinary ScienceSeoul National UniversitySeoulRepublic of Korea

Personalised recommendations