Immunotherapy of cancer via mediation of cytotoxic T lymphocytes by methionine enkephalin (MENK)

Cancer Lett. 2014 Mar 28;344(2):212-22. doi: 10.1016/j.canlet.2013.10.029. Epub 2013 Nov 26.


The aim of this study was to investigate the immunological mechanisms by which synthetic methionine enkephalin (MENK) exerts therapeutic effects on tumor growth. Our findings in vivo or in vitro show that MENK treatment either in vivo or in vitro could up-regulate the percentages of CD8+T cells, induce markers of activated T cells, increased cytotoxic activity against mouse S180 tumor cells and increase secretion of IFNγ. In addition, the adoptively transferred CD8+T cells, after either in vitro or in vivo treatment with MENK, result in significantly increased survival of S180 tumor-bearing mice and significant shrinkage in tumor growth. Opioid receptors are detected on normal CD8+T cells and exposure to MENK leads to increased expression of opioid receptors. Interaction between MENK and the opioid receptors on CD8+T cells appears to be essential for the activation of CTL, since the addition of naltrexone (NTX), an opioid receptor antagonist, significantly inhibits all of the effects of MENK. The evidence obtained indicates that the MENK-induced T cell signaling is associated with a significant up-regulation of Ca2+ influx into the cytoplasm and the translocation of NFAT2 into nucleus, and these signaling effects are also inhibited by naltrexone.

Keywords: 5-(3-carboxymethoxyphenyl)-2-(4,5-dimethylthiazoly)-3-(4-sulfophenyl)tetrazolium; Antitumor; CD8+T cells; CTL; Ca2+; Cytotoxicity; DOR; FACS; Fas ligand; FasL; GrzB; IFN-γ; MENK; MFI; MLR; MOR; MTS; Methionine enkephalin; NFAT; NTX; OGF; Opioid receptors; Prf; RT-PCR; WB; Western blot; cytotoxic T lymphocytes; delta opioid receptors; fluorescence activated cell sorting; granzyme; interferon-γ; intracellular Ca2+ concentration; mean fluorescence intensity; methionine enkephalin; mixed lymphocyte reaction; mu opioid receptors; naltrexone; nuclear factor of activated T cells; opioid growth factor; perforin; reverse transcriptase polymerase chain reaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Calcium / metabolism
  • Cell Nucleus / immunology
  • Cell Nucleus / metabolism
  • Enkephalin, Methionine / immunology
  • Enkephalin, Methionine / pharmacology*
  • Immunotherapy, Adoptive / methods*
  • Lymphocyte Activation / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Random Allocation
  • Receptors, Opioid, delta / biosynthesis
  • Receptors, Opioid, delta / immunology
  • Receptors, Opioid, mu / biosynthesis
  • Receptors, Opioid, mu / immunology
  • Sarcoma 180 / drug therapy
  • Sarcoma 180 / immunology*
  • Sarcoma 180 / therapy*
  • T-Lymphocytes, Cytotoxic / drug effects*
  • T-Lymphocytes, Cytotoxic / immunology*


  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • Enkephalin, Methionine
  • Calcium