Inhibitors of GLUT/SLC2A Enhance the Action of BCNU and Temozolomide against High-Grade Gliomas.
Glucose transport across glioblastoma membranes plays a crucial role in maintaining the enhanced glycolysis typical of high-grade gliomas and glioblastoma. We tested the ability of two inhibitors of the glucose transporters GLUT/SLC2A superfamily, indinavir (IDV) and ritonavir (RTV), and of one inhibitor of the Na/glucose antiporter type 2 (SGLT2/SLC5A2) superfamily, phlorizin (PHZ), in decreasing glucose consumption and cell proliferation of human and murine glioblastoma cells. We found in vitro that RTV, active on at least three different GLUT/SLC2A transporters, was more effective than IDV, a specific inhibitor of GLUT4/SLC2A4, both in decreasing glucose consumption and lactate production and in inhibiting growth of U87MG and Hu197 human glioblastoma cell lines and primary cultures of human glioblastoma. PHZ was inactive on the same cells. Similar results were obtained when cells were grown in adherence or as 3D multicellular tumor spheroids. RTV treatment but not IDV treatment induced AMP-activated protein kinase (AMPKα) phosphorylation that paralleled the decrease in glycolytic activity and cell growth. IDV, but not RTV, induced an increase in GLUT1/SLC2A1 whose activity could compensate for the inhibition of GLUT4/SLC2A4 by IDV. RTV and IDV pass poorly the blood brain barrier and are unlikely to reach sufficient liquoral concentrations in vivo to inhibit glioblastoma growth as single agents. Isobologram analysis of the association of RTV or IDV and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or 4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide (TMZ) indicated synergy only with RTV on inhibition of glioblastoma cells. Finally, we tested in vivo the combination of RTV and BCNU on established GL261 tumors. This drug combination increased the overall survival and allowed a five-fold reduction in the dose of BCNU.
Neurochirurgia, Dipartimento di Scienze Clinico-Chirurgiche, Diagnostiche e Pediatriche, University of Pavia - Fondazione IRCCS Policlinico S. Matteo, v.le Golgi 19, 27100 Pavia, Italy; Istituto di Genetica Molecolare IGM-CNR, via Abbiategrasso 207, 27100 Pavia, Italy.
Alberto
A
Azzalin
Department of Neuroscience Rita Levi-Montalcini, University of Turin, Neuroscience Institute Cavalieri Ottolenghi (NICO), 10043 Orbassano, (Torino), Italy.
Giulia
G
Nato
Department of Neuroscience Rita Levi-Montalcini, University of Turin, Neuroscience Institute Cavalieri Ottolenghi (NICO), 10043 Orbassano, (Torino), Italy.
Elena
E
Parmigiani
Molecular & Preclinical Imaging Centers, Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126 Torino, Italy.
Francesca
F
Garello
Department of Neuroscience Rita Levi-Montalcini, University of Turin, Neuroscience Institute Cavalieri Ottolenghi (NICO), 10043 Orbassano, (Torino), Italy.
Annalisa
A
Buffo
Neurochirurgia, Dipartimento di Scienze Clinico-Chirurgiche, Diagnostiche e Pediatriche, University of Pavia - Fondazione IRCCS Policlinico S. Matteo, v.le Golgi 19, 27100 Pavia, Italy; Istituto di Genetica Molecolare IGM-CNR, via Abbiategrasso 207, 27100 Pavia, Italy. Electronic address: lorenzo.magrassi@unipv.it.
Lorenzo
L
Magrassi
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002330:Carmustine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D005910:Glioma / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D005947:Glucose / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D051246:Glucose Transport Proteins, Facilitative; D003606:Dacarbazine; D005947:Glucose; D002330:Carmustine; D000077204:Temozolomide