title: Reversal of the glycolytic phenotype of primary effusion lymphoma cells by combined targeting of cellular metabolism and PI3K/Akt/ mTOR signaling.
abstract: PEL is a B-cell non-Hodgkin lymphoma, occurring predominantly as a lymphomatous effusion in body cavities, characterized by aggressive clinical course, with no standard therapy. Based on previous reports that PEL cells display a Warburg phenotype, we hypothesized that the highly hypoxic environment in which they grow in vivo makes them more reliant on glycolysis, and more vulnerable to drugs targeting this pathway. We established here that indeed PEL cells in hypoxia are more sensitive to glycolysis inhibition. Furthermore, since PI3K/Akt/mTOR has been proposed as a drug target in PEL, we ascertained that pathway-specific inhibitors, namely the dual PI3K and mTOR inhibitor, PF-04691502, and the Akt inhibitor, Akti 1/2, display improved cytotoxicity to PEL cells in hypoxic conditions. Unexpectedly, we found that these drugs reduce lactate production/extracellular acidification rate, and, in combination with the glycolysis inhibitor 2-deoxyglucose (2-DG), they shift PEL cells metabolism from aerobic glycolysis towards oxidative respiration. Moreover, the associations possess strong synergistic cytotoxicity towards PEL cells, and thus may reduce adverse reaction in vivo, while displaying very low toxicity to normal lymphocytes. Finally, we showed that the association of 2-DG and PF-04691502 maintains its cytotoxic and proapoptotic effect also in PEL cells co-cultured with human primary mesothelial cells, a condition known to mimic the in vivo environment and to exert a protective and pro-survival action. All together, these results provide a compelling rationale for the clinical development of new therapies for the treatment of PEL, based on combined targeting of glycolytic metabolism and constitutively activated signaling pathways.
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mediani
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Gibellini
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy.|Department of Morphology, Surgery and Experimental Medicine, Section of Anatomy and Histology and LTTA Center, University of Ferrara, Ferrara, Italy.
authors.forename: Jessika
authors.initials: J
authors.lastname: Bertacchini
authors.affiliation: Department of Woman's and Child's Health and Institute of Pediatric Research - Città della Speranza Foundation, University of Padova, Padova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Frasson
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Bosco
authors.affiliation: Department of Woman's and Child's Health and Institute of Pediatric Research - Città della Speranza Foundation, University of Padova, Padova, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Accordi
authors.affiliation: Department of Woman's and Child's Health and Institute of Pediatric Research - Città della Speranza Foundation, University of Padova, Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bonora
authors.affiliation: Immunology and Molecular Oncology, Veneto Institute of Oncology, IOV IRCCS, Padova, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Calabrò
authors.affiliation: Immunology and Molecular Oncology, Veneto Institute of Oncology, IOV IRCCS, Padova, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Mattiolo
authors.affiliation: Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sgarbi
authors.affiliation: Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Baracca
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.affiliation: Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Riva
authors.affiliation: Department of Chemistry, University of Bologna, Bologna, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Rampazzo
authors.affiliation: Department of Chemistry, University of Bologna, Bologna, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Petrizza
authors.affiliation: Department of Chemistry, University of Bologna, Bologna, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Prodi
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Anatomy and Histology and LTTA Center, University of Ferrara, Ferrara, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Milani
authors.affiliation: Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Luppi
authors.affiliation: Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Potenza
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Anto
authors.initials: A
authors.lastname: De Pol
authors.affiliation: Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Cocco
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Anatomy and Histology and LTTA Center, University of Ferrara, Ferrara, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Capitani
authors.affiliation: Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Marmiroli
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003847:Deoxyglucose / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D040081:Protein Array Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D003847:Deoxyglucose; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011728:Pyridones; D011743:Pyrimidines; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; C570662:2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one; C546842:MTOR protein, human
keywords: PEL/non-Hodgkin lymphoma; PI3K/Akt/mTOR inhibitors; Warburg phenotype; glycolyis inhibitors; hypoxia