Protodynamic intracellular acidification by cis-urocanic acid promotes apoptosis of melanoma cells in vitro and in vivo

J Invest Dermatol. 2010 Oct;130(10):2431-9. doi: 10.1038/jid.2010.151. Epub 2010 Jun 3.


The extracellular tumor microenvironment is acidified, whereas the intracellular pH of tumor and stromal cells is neutral. cis-Urocanic acid (cis-UCA), an endogenous compound of the skin, can acidify the cytosol by transporting protons into the cells. This phenomenon, termed the protodynamic concept, was studied here in human cancer cells. cis-UCA dose-dependently reduced the number of viable human melanoma, cervical carcinoma, and fibrosarcoma cells at weakly acidic extracellular pH. The intracellular pH decreased by up to 0.5 pH units in a concentration-dependent manner with 0.3-30 m cis-UCA at extracellular pH 6.5 but not at pH 7.4. Under the same conditions, 30 mM cis-UCA induced annexin-V binding and activation of caspase-3 in A2058 melanoma cells as signs of apoptotic cell death. Finally, growth of human melanoma xenografts in SCID mice was suppressed by 60% following intratumoral injection of cis-UCA. Accordingly, the percentage of tumor necrosis and active caspase-3-immunopositive cells increased, whereas proliferation activity decreased. These results identify cis-UCA as an anticancer agent inhibiting melanoma growth by immediate intracellular acidification followed by apoptotic cell death in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acids / metabolism*
  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cell Line, Transformed
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Fibrosarcoma / drug therapy
  • Fibrosarcoma / pathology
  • HeLa Cells
  • Humans
  • Hydrogen-Ion Concentration / drug effects
  • In Vitro Techniques
  • Melanoma / drug therapy*
  • Melanoma / pathology
  • Mice
  • Mice, SCID
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / pathology
  • Urocanic Acid / pharmacology*
  • Uterine Cervical Neoplasms / drug therapy
  • Uterine Cervical Neoplasms / pathology
  • Xenograft Model Antitumor Assays


  • Acids
  • Urocanic Acid