A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Protodynamic Intracellular Acidification by cis-Urocanic Acid Promotes Apoptosis of Melanoma Cells In Vitro and In Vivo
Tekijät: Laihia JK, Kallio JP, Taimen P, Kujari H, Kahari VM, Leino L
Kustantaja: NATURE PUBLISHING GROUP
Julkaisuvuosi: 2010
Journal: Journal of Investigative Dermatology
Tietokannassa oleva lehden nimi: JOURNAL OF INVESTIGATIVE DERMATOLOGY
Lehden akronyymi: J INVEST DERMATOL
Numero sarjassa: 10
Vuosikerta: 130
Numero: 10
Aloitussivu: 2431
Lopetussivu: 2439
Sivujen määrä: 9
ISSN: 0022-202X
DOI: https://doi.org/10.1038/jid.2010.151
Tiivistelmä
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 mM 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.
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 mM 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.
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