title: pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity.
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.
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di Sanità, Rome, Italy. angelo.demilito@iss.it
authors.forename: Angelo
authors.initials: A
authors.lastname: De Milito
authors.forename: Rossella
authors.initials: R
authors.lastname: Canese
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Marino
authors.forename: Martina
authors.initials: M
authors.lastname: Borghi
authors.forename: Manuela
authors.initials: M
authors.lastname: Iero
authors.forename: Antonello
authors.initials: A
authors.lastname: Villa
authors.forename: Giulietta
authors.initials: G
authors.lastname: Venturi
authors.forename: Francesco
authors.initials: F
authors.lastname: Lozupone
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Iessi
authors.forename: Mariantonia
authors.initials: M
authors.lastname: Logozzi
authors.forename: Pamela
authors.initials: P
authors.lastname: Della Mina
authors.forename: Mario
authors.initials: M
authors.lastname: Santinami
authors.forename: Monica
authors.initials: M
authors.lastname: Rodolfo
authors.forename: Franca
authors.initials: F
authors.lastname: Podo
authors.forename: Licia
authors.initials: L
authors.lastname: Rivoltini
authors.forename: Stefano
authors.initials: S
authors.lastname: Fais
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D064098:Esomeprazole / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D006863:Hydrogen-Ion Concentration; D008279:Magnetic Resonance Imaging; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D054328:Proton Pump Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D054328:Proton Pump Inhibitors; D064098:Esomeprazole