Clostridium butyricum MIYAIRI 588 shows antitumor effects by enhancing the release of TRAIL from neutrophils through MMP-8

Int J Oncol. 2013 Mar;42(3):903-11. doi: 10.3892/ijo.2013.1790. Epub 2013 Jan 23.


Bacillus Calmette-Guérin (BCG) intravesical therapy against superficial bladder cancer is one of the most successful immunotherapies in cancer, though the precise mechanism has not been clarified. Recent studies have demonstrated urinary tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) levels to be higher in BCG-responsive patients than non-responders and shown that polymorphonuclear neutrophils (PMNs) migrating to the bladder after BCG instillation release large amounts of TRAIL. To establish a safer and more effective intravesical therapy than BCG, we examined whether other bacteria induced similar effects. We stimulated PMNs or peripheral blood mononuclear cells (PBMCs) with BCG or other bacteria, and then aliquots of the culture supernatants or cell lysates were assayed for TRAIL. We examined the signaling pathway regulating the release of TRAIL from PMNs and evaluated the antitumor effects of BCG or other bacteria in vitro and in vivo. We have found that Clostridium butyricum MIYAIRI 588 (CBM588) induces the release of endogenous TRAIL from PMNs as well as BCG. In addition, we have shown that matrix metalloproteinase 8 (MMP-8) is one of the key factors responsible for the release. Interestingly, TLR2/4 signaling pathway has been suggested to be important for the release of TRAIL by MMP-8. CBM588 has been proven to be as effective as BCG against cancer cells by inducing apoptosis in vivo as well as in vitro. Taken together, these results strongly suggest that CBM588 is promising for a safer and more effective therapy against bladder cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • BCG Vaccine / therapeutic use
  • Cell Line, Tumor
  • Clostridium butyricum / physiology*
  • Female
  • HEK293 Cells
  • Humans
  • Kidney Neoplasms / therapy
  • Lung Neoplasms / therapy
  • Matrix Metalloproteinase 8 / genetics
  • Matrix Metalloproteinase 8 / metabolism*
  • Matrix Metalloproteinase 9 / genetics
  • Mice
  • Mice, Inbred C3H
  • Neoplasm Transplantation
  • Neutrophils / metabolism*
  • Probiotics / pharmacology*
  • RNA Interference
  • RNA, Small Interfering
  • Sequence Analysis, DNA
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / metabolism
  • Urinary Bladder Neoplasms / therapy
  • Xenograft Model Antitumor Assays


  • BCG Vaccine
  • RNA, Small Interfering
  • TLR2 protein, human
  • TLR4 protein, human
  • TNF-Related Apoptosis-Inducing Ligand
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Matrix Metalloproteinase 8
  • Matrix Metalloproteinase 9