Protodynamic intracellular acidification by cis-urocanic acid promotes apoptosis of melanoma cells in vitro and in vivo.
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.
Laihia
Jarmo K
JK
R&D, BioCis Pharma Ltd, Turku, Finland. jarmo.laihia@biocis.com
Kallio
Janne P
JP
Taimen
Pekka
P
Kujari
Harry
H
Kähäri
Veli-Matti
VM
Leino
Lasse
L
D000143:Acids / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D066298:In Vitro Techniques; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014560:Urocanic Acid / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000143:Acids; D014560:Urocanic Acid