Reversal of the glycolytic phenotype of primary effusion lymphoma cells by combined targeting of cellular metabolism and PI3K/Akt/ mTOR signaling
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Laura Mediani1,*, Federica Gibellini1,*, Jessika Bertacchini1,8, Chiara Frasson2, Raffaella Bosco1, Benedetta Accordi2, Giuseppe Basso2, Massimo Bonora3, Maria Luisa Calabrò4, Adriana Mattiolo4, Gianluca Sgarbi5, Alessandra Baracca5, Paolo Pinton3, Giovanni Riva6, Enrico Rampazzo7, Luca Petrizza7, Luca Prodi7, Daniela Milani8, Mario Luppi6, Leonardo Potenza6, Anto De Pol1, Lucio Cocco5, Silvano Capitani8, Sandra Marmiroli1
1Department of Surgery, Medicine, Dentistry and Morphology, University of Modena and Reggio Emilia, Modena, Italy
2Department of Woman’s and Child’s Health and Institute of Pediatric Research - Città della Speranza Foundation, University of Padova, Padova, Italy
3Department of Morphology, Surgery and Experimental Medicine Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy
4Immunology and Molecular Oncology, Veneto Institute of Oncology, IOV IRCCS, Padova, Italy
5Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
6Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy
7Department of Chemistry, University of Bologna, Bologna, Italy
8Department of Morphology, Surgery and Experimental Medicine, Section of Anatomy and Histology and LTTA Center, University of Ferrara, Ferrara, Italy
*These authors have contributed equally to this work
Sandra Marmiroli, e-mail: [email protected]
Silvano Capitani, e-mail: [email protected]
Keywords: PEL/non-Hodgkin lymphoma, glycolyis inhibitors, Warburg phenotype, hypoxia, PI3K/Akt/mTOR inhibitors
Received: May 11, 2015 Accepted: October 27, 2015 Published: November 06, 2015
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.
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