pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity

Authors

  • Angelo De Milito,

    Corresponding author
    1. Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di Sanità, Rome, Italy
    • Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
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    • Tel.: +39-06-49902153; Fax: +39-06-49902436-3691

  • Rossella Canese,

    1. Department of Cell Biology and Neurosciences, Unit of Molecular and Cellular Imaging, Istituto Superiore di Sanità, Rome, Italy
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  • Maria Lucia Marino,

    1. Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di Sanità, Rome, Italy
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  • Martina Borghi,

    1. Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di Sanità, Rome, Italy
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  • Manuela Iero,

    1. Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
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  • Antonello Villa,

    1. Microscopy and Image Analysis Consortium, University of Milano-Bicocca, Monza, Italy
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  • Giulietta Venturi,

    1. Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di Sanità, Rome, Italy
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  • Francesco Lozupone,

    1. Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di Sanità, Rome, Italy
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  • Elisabetta Iessi,

    1. Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di Sanità, Rome, Italy
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  • Mariantonia Logozzi,

    1. Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di Sanità, Rome, Italy
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  • Pamela Della Mina,

    1. Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
    2. Microscopy and Image Analysis Consortium, University of Milano-Bicocca, Monza, Italy
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  • Mario Santinami,

    1. Unit of Melanoma and Sarcoma, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
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  • Monica Rodolfo,

    1. Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
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  • Franca Podo,

    1. Department of Cell Biology and Neurosciences, Unit of Molecular and Cellular Imaging, Istituto Superiore di Sanità, Rome, Italy
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  • Licia Rivoltini,

    1. Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
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    • Licia Rivoltini and Stefano Fais have shared senior authorship.

  • Stefano Fais

    1. Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di Sanità, Rome, Italy
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    • Licia Rivoltini and Stefano Fais have shared senior authorship.


Abstract

Metastatic melanoma is associated with poor prognosis and still limited therapeutic options. An innovative treatment approach for this disease is represented by targeting acidosis, a feature characterizing tumor microenvironment and playing an important role in cancer malignancy. Proton pump inhibitors (PPI), such as esomeprazole (ESOM) are prodrugs functionally activated by acidic environment, fostering pH neutralization by inhibiting proton extrusion. We used human melanoma cell lines and xeno-transplated SCID mice to provide preclinical evidence of ESOM antineoplastic activity. Human melanoma cell lines, characterized by different mutation and signaling profiles, were treated with ESOM in different pH conditions and evaluated for proliferation, viability and cell death. SCID mice engrafted with human melanoma were used to study ESOM administration effects on tumor growth and tumor pH by magnetic resonance spectroscopy (MRS). ESOM inhibited proliferation of melanoma cells in vitro and induced a cytotoxicity strongly boosted by low pH culture conditions. ESOM-induced tumor cell death occurred via rapid intracellular acidification and activation of several caspases. Inhibition of caspases activity by pan-caspase inhibitor z-vad-fmk completely abrogated the ESOM-induced cell death. ESOM administration (2.5 mg kg−1) to SCID mice engrafted with human melanoma reduced tumor growth, consistent with decrease of proliferating cells and clear reduction of pH gradients in tumor tissue. Moreover, systemic ESOM administration dramatically increased survival of human melanoma-bearing animals, in absence of any relevant toxicity. These data show preclinical evidence supporting the use of PPI as novel therapeutic strategy for melanoma, providing the proof of concept that PPI target human melanoma modifying tumor pH gradients.

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