Protodynamic Intracellular Acidification by cis-Urocanic Acid Promotes Apoptosis of Melanoma Cells In Vitro and In Vivo Jarmo K. Laihia, Janne P. Kallio,

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Protodynamic Intracellular Acidification by cis-Urocanic Acid Promotes Apoptosis of Melanoma Cells In Vitro and In Vivo Jarmo K. Laihia, Janne P. Kallio, Pekka Taimen, Harry Kujari, Veli-Matti Kähäri, Lasse Leino Journal of Investigative Dermatology Volume 130, Issue 10, Pages 2431-2439 (October 2010) DOI: 10.1038/jid.2010.151 Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 The protodynamic anticancer effect of cis-UCA. (a) The dose response of viability (MTS assay) of three cancer cell lines after a 2-day cis-UCA treatment at pH 6.5 (mean from duplicate incubations). (b) A2058 melanoma cells were adapted to pH 7.3 or pH 6.7 for 3 days and an equal number of viable cells was subsequently cultured at pH 7.4 or pH 6.5 for 44hours with or without cis-UCA (mean±SD from triplicate measurements). (c) A2058 cells were treated with cis-UCA at pH 6.5 for 20hours (left) and an equal number of viable cells was further cultured without cis-UCA for 44hours (right). Cell viability was dertermined as the number of trypan blue-negative cells. (d) The intracellular pH of A2058 cells in pH-adjusted buffer solutions containing the indicated concentrations of cis-UCA (left) or trans-UCA (right). Inset: BCECF calibration curve. Journal of Investigative Dermatology 2010 130, 2431-2439DOI: (10.1038/jid.2010.151) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Induction of apoptosis by cis-UCA in A2058 melanoma cells. (a) Effect of CPT on cell viability at 48hours. (b) Annexin-V/propidium iodide binding in cells treated with CPT, cis-UCA, or trans-UCA for 18hours. (c) Caspase-3-like activity at pH 6.5 after 24hours. Inset: Linearity of pNA absorption. (d) Western blots showing caspase-3 cleavage products (single band in 10% gel) induced at 24hours (upper panel) in a concentration-dependent manner (lower panel). (e) Temporal induction of caspase-3-like activity (mean±SD from triplicate determinations in four independent experiments). Each time point was assayed at least twice. The medium was not changed during these experiments. (f) The number of trypan blue-negative viable cells versus control incubation and the (g) pH of the medium measured after each incubation. Journal of Investigative Dermatology 2010 130, 2431-2439DOI: (10.1038/jid.2010.151) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 cis-UCA inhibits melanoma growth in vivo. Subcutaneous melanoma tumors were established by injecting 2 × 106 A2058 cells in the back of SCID mice and allowed to grow for 2 weeks. The tumors were then injected with 50μl cis-UCA (30mM), CPT (1μM), or PBS (control) three times a week. Development of (a) tumor area and (b) tumor weight were then followed (mean, SD). The data points have been normalized to unity in tumor sizes at day 0 (n=5 in each group). Journal of Investigative Dermatology 2010 130, 2431-2439DOI: (10.1038/jid.2010.151) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Histological and immunohistochemical examination of A2058 melanoma tumors from SCID/SCID mice. (a) Identification of necrosis (light brown areas, left-hand panels; bar=500μm) bordered by apoptotic cells (right-hand panels; bar=50μm). Arrowheads: Examples of cleaved caspase-3-positive cells. (b) Ki-67 staining of tumor sections. One representative section from groups A and B is shown. Bar=50μm (c) A graph showing the percentage of necrotic tumor tissue. (d) The percentages of Ki-67-positive tumor cells. The amount of positive cells was determined from areas containing the highest proportion of immunopositive cells in the sections. Journal of Investigative Dermatology 2010 130, 2431-2439DOI: (10.1038/jid.2010.151) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 The physicochemical background of the protodynamic action of cis-UCA. (From left to right) Photo-isomerization of free (extracellular) UCA normally takes place in the acidic skin environment. At a mildly acidic pH, cis-UCA preserves one of the protons at the imidazolyl moiety. After penetration of the electroneutral molecule into the cell cytosol with a close-to-neutral pH, the proton is released and the cytosol is acidified. Journal of Investigative Dermatology 2010 130, 2431-2439DOI: (10.1038/jid.2010.151) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions