title: Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma.
abstract: The human malignant mesothelioma (HMM) is characterized by a chemoresistant and immunosuppressive phenotype. An effective strategy to restore chemosensitivity and immune reactivity against HMM is lacking. We investigated whether the use of zoledronic acid is an effective chemo-immunosensitizing strategy. We compared primary HMM samples with non-transformed mesothelial cells. HMM cells had higher rate of cholesterol and isoprenoid synthesis, constitutive activation of Ras/extracellular signal-regulated kinase1/2 (ERK1/2)/hypoxia inducible factor-1α (HIF-1α) pathway and up-regulation of the drug efflux transporter P-glycoprotein (Pgp). By decreasing the isoprenoid supply, zoledronic acid down-regulated the Ras/ERK1/2/HIF-1α/Pgp axis and chemosensitized the HMM cells to Pgp substrates. The HMM cells also produced higher amounts of kynurenine, decreased the proliferation of T-lymphocytes and expanded the number of T-regulatory (Treg) cells. Kynurenine synthesis was due to the transcription of the indoleamine 1,2 dioxygenase (IDO) enzyme, consequent to the activation of the signal transducer and activator of transcription-3 (STAT3). By reducing the activity of the Ras/ERK1/2/STAT3/IDO axis, zoledronic acid lowered the kyurenine synthesis and the expansion of Treg cells, and increased the proliferation of T-lymphocytes. Thanks to its ability to decrease Ras/ERK1/2 activity, which is responsible for both Pgp-mediated chemoresistance and IDO-mediated immunosuppression, zoledronic acid is an effective chemo-immunosensitizing agent in HMM cells.
authors.affiliation: Department of Oncology, University of Torino, Italy.
authors.forename: Iris Chiara
authors.initials: IC
authors.lastname: Salaroglio
authors.affiliation: Department of Oncology, University of Torino, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Campia
authors.affiliation: Department of Oncology, University of Torino, Italy.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kopecka
authors.affiliation: Department of Oncology, University of Torino, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Gazzano
authors.affiliation: S.C. Anatomia Patologica, Azienda Ospedaliera S.S. Antonio e Biagio, Alessandria, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Orecchia
authors.affiliation: Department of Oncology, University of Torino, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Ghigo
authors.affiliation: Department of Oncology, University of Torino, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Riganti
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D013729:Terpenes / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000077211:Zoledronic Acid; D018631:ras Proteins / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D004164:Diphosphonates; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D050796:STAT3 Transcription Factor; D013729:Terpenes; D007737:Kynurenine; D000077211:Zoledronic Acid; D002784:Cholesterol; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins