title: Lansoprazole induces sensitivity to suboptimal doses of paclitaxel in human melanoma.
abstract: Tumor acidity is now considered an important determinant of drug-resistance and tumor progression, and anti-acidic approaches, such as Proton Pump inhibitors (PPIs), have demonstrated promising antitumor and chemo-sensitizing efficacy. The main purpose of the present study was to evaluate the possible PPI-induced sensitization of human melanoma cells to Paclitaxel (PTX). Our results show that PTX and the PPI Lansoprazole (LAN) combination was extremely efficient against metastatic melanoma cells, as compared to the single treatments, both in vitro and in vivo. We also showed that acidity plays an important role on the anti-tumor activity of these drugs, being detrimental for PTX activity, while crucial for the synergistic effect of PTX following pretreatment with LAN, due to its nature of pro-drug needing protonation for a full activation. We obtained straightforward results in a human melanoma xenograft model combining well tolerated LAN doses with suboptimal and poorly toxic doses of PTX. With this study we provide a clear evidence that the PPI LAN may be included in new combined therapy of human melanoma together with low doses of PTX.
authors.affiliation: Anti-Tumour Drugs Section, Department of Drug Research and Medicines Evaluation, National Institute of Health Viale Regina Elena, 299 00161 Rome, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Azzarito
authors.affiliation: Anti-Tumour Drugs Section, Department of Drug Research and Medicines Evaluation, National Institute of Health Viale Regina Elena, 299 00161 Rome, Italy.
authors.forename: Giulietta
authors.initials: G
authors.lastname: Venturi
authors.affiliation: Department of Hematology, Oncology and Molecular Biology, National Institute of Health Viale Regina Elena, 299 00161 Rome, Italy.
authors.forename: Albino
authors.initials: A
authors.lastname: Cesolini
authors.affiliation: Anti-Tumour Drugs Section, Department of Drug Research and Medicines Evaluation, National Institute of Health Viale Regina Elena, 299 00161 Rome, Italy. Electronic address: stefano.fais@iss.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fais
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D064747:Lansoprazole / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D017239:Paclitaxel / Q000494:pharmacology*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D017239:Paclitaxel
keywords: Lansoprazole; Melanoma; Paclitaxel; Proton pump inhibitors