title: Zoledronic acid restores doxorubicin chemosensitivity and immunogenic cell death in multidrug-resistant human cancer cells.
abstract: Durable tumor cell eradication by chemotherapy is challenged by the development of multidrug-resistance (MDR) and the failure to induce immunogenic cell death. The aim of this work was to investigate whether MDR and immunogenic cell death share a common biochemical pathway eventually amenable to therapeutic intervention. We found that mevalonate pathway activity, Ras and RhoA protein isoprenylation, Ras- and RhoA-downstream signalling pathway activities, Hypoxia Inducible Factor-1alpha activation were significantly higher in MDR+ compared with MDR- human cancer cells, leading to increased P-glycoprotein expression, and protection from doxorubicin-induced cytotoxicity and immunogenic cell death. Zoledronic acid, a potent aminobisphosphonate targeting the mevalonate pathway, interrupted Ras- and RhoA-dependent downstream signalling pathways, abrogated the Hypoxia Inducible Factor-1alpha-driven P-glycoprotein expression, and restored doxorubicin-induced cytotoxicity and immunogenic cell death in MDR+ cells. Immunogenic cell death recovery was documented by the ability of dendritic cells to phagocytise MDR+ cells treated with zoledronic acid plus doxorubicin, and to recruit anti-tumor cytotoxic CD8+ T lymphocytes. These data indicate that MDR+ cells have an hyper-active mevalonate pathway which is targetable with zoledronic acid to antagonize their ability to withstand chemotherapy-induced cytotoxicity and escape immunogenic cell death.
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy. chiara.riganti@unito.it
authors.forename: Chiara
authors.initials: C
authors.lastname: Riganti
authors.forename: Barbara
authors.initials: B
authors.lastname: Castella
authors.forename: Joanna
authors.initials: J
authors.lastname: Kopecka
authors.forename: Ivana
authors.initials: I
authors.lastname: Campia
authors.forename: Marta
authors.initials: M
authors.lastname: Coscia
authors.forename: Gianpiero
authors.initials: G
authors.lastname: Pescarmona
authors.forename: Amalia
authors.initials: A
authors.lastname: Bosia
authors.forename: Dario
authors.initials: D
authors.lastname: Ghigo
authors.forename: Massimo
authors.initials: M
authors.lastname: Massaia
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism; D008954:Models, Biological; D010587:Phagocytosis / Q000187:drug effects; D054876:Prenylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013729:Terpenes / Q000378:metabolism; D000077211:Zoledronic Acid; D018631:ras Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004164:Diphosphonates; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D013729:Terpenes; D000077211:Zoledronic Acid; D004317:Doxorubicin; D002784:Cholesterol; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; D008798:Mevalonic Acid