PMID- 28319810
OWN - NLM
STAT- MEDLINE
DCOM- 20170807
LR  - 20230131
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 19
IP  - 4
DP  - 2017 Apr
TI  - Inhibitors of GLUT/SLC2A Enhance the Action of BCNU and Temozolomide against 
      High-Grade Gliomas.
PG  - 364-373
LID - S1476-5586(16)30347-5 [pii]
LID - 10.1016/j.neo.2017.02.009 [doi]
AB  - 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 (AMPKalpha) 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.
CI  - Copyright (c) 2017 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Azzalin, Alberto
AU  - Azzalin A
AD  - 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.
FAU - Nato, Giulia
AU  - Nato G
AD  - Department of Neuroscience Rita Levi-Montalcini, University of Turin, 
      Neuroscience Institute Cavalieri Ottolenghi (NICO), 10043 Orbassano, (Torino), 
      Italy.
FAU - Parmigiani, Elena
AU  - Parmigiani E
AD  - Department of Neuroscience Rita Levi-Montalcini, University of Turin, 
      Neuroscience Institute Cavalieri Ottolenghi (NICO), 10043 Orbassano, (Torino), 
      Italy.
FAU - Garello, Francesca
AU  - Garello F
AD  - Molecular & Preclinical Imaging Centers, Department of Molecular Biotechnology 
      and Health Sciences, University of Torino, Via Nizza 52, 10126 Torino, Italy.
FAU - Buffo, Annalisa
AU  - Buffo A
AD  - Department of Neuroscience Rita Levi-Montalcini, University of Turin, 
      Neuroscience Institute Cavalieri Ottolenghi (NICO), 10043 Orbassano, (Torino), 
      Italy.
FAU - Magrassi, Lorenzo
AU  - Magrassi L
AD  - 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.
LA  - eng
PT  - Journal Article
DEP - 20170319
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (Glucose Transport Proteins, Facilitative)
RN  - 7GR28W0FJI (Dacarbazine)
RN  - IY9XDZ35W2 (Glucose)
RN  - U68WG3173Y (Carmustine)
RN  - YF1K15M17Y (Temozolomide)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Alkylating/*pharmacology
MH  - Biological Transport/drug effects
MH  - Carmustine/*pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Dacarbazine/*analogs & derivatives/pharmacology
MH  - Disease Models, Animal
MH  - Drug Synergism
MH  - Female
MH  - Glioma/diagnosis/drug therapy/metabolism/mortality
MH  - Glucose/metabolism
MH  - Glucose Transport Proteins, Facilitative/*antagonists & inhibitors/metabolism
MH  - Humans
MH  - Mice
MH  - Temozolomide
MH  - Xenograft Model Antitumor Assays
PMC - PMC5358953
EDAT- 2017/03/21 06:00
MHDA- 2017/08/08 06:00
PMCR- 2017/03/19
CRDT- 2017/03/21 06:00
PHST- 2016/12/21 00:00 [received]
PHST- 2017/02/16 00:00 [revised]
PHST- 2017/02/21 00:00 [accepted]
PHST- 2017/03/21 06:00 [pubmed]
PHST- 2017/08/08 06:00 [medline]
PHST- 2017/03/21 06:00 [entrez]
PHST- 2017/03/19 00:00 [pmc-release]
AID - S1476-5586(16)30347-5 [pii]
AID - 10.1016/j.neo.2017.02.009 [doi]
PST - ppublish
SO  - Neoplasia. 2017 Apr;19(4):364-373. doi: 10.1016/j.neo.2017.02.009. Epub 2017 Mar 
      19.