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pH‐dependentantitumor activity ofproton pumpinhibitors againsthuman melanoma ismediated byinhibition of tumoracidity Angelo De MilitoRossella CaneseMaria Lucia Marino2009 год

pH‐dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity
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Аннотация: 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.
Год издания: 2009
Авторы: Angelo De Milito, Rossella Canese, Maria Lucia Marino, Martina Borghi, Manuela Iero, Antonello Villa, Giulietta Venturi, Francesco Lozupone, Elisabetta Iessi, Mariantonia Logozzi, Pamela Della Mina, Mario Santinami, Monica Rodolfo, Franca Podo, Licia Rivoltini, Stefano Fais
Издательство: Wiley
Источник: International Journal of Cancer
Ключевые слова: ATP Synthase and ATPases Research, Ion Transport and Channel Regulation, Enzyme function and inhibition
Другие ссылки: International Journal of Cancer (HTML)
PubMed (HTML)