title: Antitumor effect of combination of the inhibitors of two new oncotargets: proton pumps and reverse transcriptase.
abstract: Tumor therapy needs new approaches in order to improve efficacy and reduce toxicity of the current treatments. The acidic microenvironment and the expression of high levels of endogenous non-telomerase reverse transcriptase (RT) are common features of malignant tumor cells. The anti-acidic proton pump inhibitor Lansoprazole (LAN) and the non-nucleoside RT inhibitor Efavirenz (EFV) have shown independent antitumor efficacy. LAN has shown to counteract drug tumor resistance. We tested the hypothesis that combination of LAN and EFV may improve the overall antitumor effects. We thus pretreated human metastatic melanoma cells with LAN and then with EFV, both in 2D and 3D spheroid models. We evaluated the treatment effect by proliferation and cell death/apoptosis assays in classical and in pulse administration experiments. The action of EFV was negatively affected by the tumor microenvironmental acidity, and LAN pretreatment overcame the problem. LAN potentiated the cytotoxicity of EFV to melanoma cells and, when administered during the drug interruption period, prevented the replacement of tumor cell growth.This study supports the implementation of the current therapies with combination of Proton Pumps and Reverse Transcriptase inhibitors.
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, National Institute of Health, Rome, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Lugini
authors.affiliation: Department of Servizio Biologico e per la Gestione della Sperimentazione Animale (SBGSA), National Institute of Health, Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Sciamanna
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, National Institute of Health, Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Federici
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, National Institute of Health, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Iessi
authors.affiliation: Stabilimento Allevatore Fornitore Utilizzatore (SAFU) Department, Regina Elena Cancer Institute, Rome, Italy.
authors.forename: Enrico Pierluigi
authors.initials: EP
authors.lastname: Spugnini
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, National Institute of Health, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fais
mesh_terms: D000480:Alkynes; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003521:Cyclopropanes; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D006801:Humans; D064747:Lansoprazole / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D018874:Spheroids, Cellular / Q000166:cytology / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D054328:Proton Pump Inhibitors; D018894:Reverse Transcriptase Inhibitors; D064747:Lansoprazole; C098320:efavirenz
keywords: efavirenz; lansoprazole; proton pump inhibitors; reverse transcriptase; tumor acidity