Long-term in vitro treatment of human glioblastoma cells with temozolomide increases resistance in vivo through up-regulation of GLUT transporter and aldo-keto reductase enzyme AKR1C expression.
Glioblastoma (GBM) is the most frequent malignant glioma. Treatment of GBM patients is multimodal with maximum surgical resection, followed by concurrent radiation and chemotherapy with the alkylating drug temozolomide (TMZ). The present study aims to identify genes implicated in the acquired resistance of two human GBM cells of astrocytic origin, T98G and U373, to TMZ. Resistance to TMZ was induced by culturing these cells in vitro for months with incremental TMZ concentrations up to 1 mM. Only partial resistance to TMZ has been achieved and was demonstrated in vivo in immunocompromised mice bearing orthotopic U373 and T98G xenografts. Our data show that long-term treatment of human astroglioma cells with TMZ induces increased expression of facilitative glucose transporter/solute carrier GLUT/SLC2A family members, mainly GLUT-3, and of the AKR1C family of proteins. The latter proteins are phase 1 drug-metabolizing enzymes involved in the maintenance of steroid homeostasis, prostaglandin metabolism, and metabolic activation of polycyclic aromatic hydrocarbons. GLUT-3 has been previously suggested to exert roles in GBM neovascularization processes, and TMZ was found to exert antiangiogenic effects in experimental gliomas. AKR1C1 was previously shown to be associated with oncogenic potential, with proproliferative effects similar to AKR1C3 in the latter case. Both AKR1C1 and AKR1C2 proteins are involved in cancer pro-proliferative cell chemoresistance. Selective targeting of GLUT-3 in GBM and/or AKR1C proteins (by means of jasmonates, for example) could thus delay the acquisition of resistance to TMZ of astroglioma cells in the context of prolonged treatment with this drug.
Le Calvé
Benjamin
B
Laboratoire de Toxicologie, Institut de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
Rynkowski
Michal
M
Le Mercier
Marie
M
Bruyère
Céline
C
Lonez
Caroline
C
Gras
Thierry
T
Haibe-Kains
Benjamin
B
Bontempi
Gianluca
G
Decaestecker
Christine
C
Ruysschaert
Jean-Marie
JM
Kiss
Robert
R
Lefranc
Florence
F
D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000449:Aldehyde Reductase; D000074408:Aldo-Keto Reductases; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics* / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000077204:Temozolomide; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D051246:Glucose Transport Proteins, Facilitative; D003606:Dacarbazine; D000429:Alcohol Oxidoreductases; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; C000614209:AKR7A5 protein, mouse; D000077204:Temozolomide
Cancer Res. 2007 Jan 15;67(2):580-4
17234766
Biochem Biophys Res Commun. 1994 Sep 30;203(3):1622-8
7945312
Cancer Res. 1990 Oct 1;50(19):6119-29
2205376
Cancer Chemother Pharmacol. 2009 Oct;64(5):1053-8
19597728
Nat Genet. 2006 Apr;38(4):452-7
16550171
Mol Cancer. 2006 Dec 02;5:67
17140455
Mol Cancer Ther. 2006 Sep;5(9):2182-92
16985051
Eur J Cancer. 2009 Nov;45(16):2893-905
19679463
Exp Cell Res. 2008 Oct 1;314(16):2985-98
18598694
Am J Clin Pathol. 1992 Jun;97(6):776-86
1375804
Oncogene. 2007 Jan 11;26(2):186-97
16819506
Carcinogenesis. 2009 Oct;30(10):1813-20
19696165
Nat Rev Cancer. 2004 Nov;4(11):891-9
15516961
Clin Cancer Res. 2008 Dec 15;14(24):8205-12
19088037
Brain Res Mol Brain Res. 1994 Nov;27(1):51-7
7877454
Cancer Res. 2008 Jul 15;68(14):5706-15
18632623
J Neuropathol Exp Neurol. 2001 Sep;60(9):863-71
11556543
Neoplasia. 2010 Jan;12(1):69-79
20072655
Neoplasia. 2008 Dec;10(12):1383-92
19048117
Expert Rev Anticancer Ther. 2007 Nov;7(11):1581-90
18020926
Lab Invest. 2005 Dec;85(12):1457-70
16170333
Int J Cancer. 2007 May 1;120(9):2019-27
17266043
J Clin Oncol. 2008 Jun 20;26(18):3015-24
18565887
Am J Kidney Dis. 1999 Jul;34(1):189-202
10401038
Cancer Res. 2007 May 1;67(9):4467-73
17483362
Cancer Res. 2005 Jul 15;65(14):6394-400
16024643
Neoplasia. 2009 May;11(5):485-96
19412433
Mol Cell Endocrinol. 2004 Feb 27;215(1-2):63-72
15026176
Cancer Res. 2001 Mar 15;61(6):2744-50
11289157
Lancet Oncol. 2009 May;10(5):459-66
19269895
Clin Cancer Res. 2006 Aug 1;12(15):4738-46
16899625
Biochem Pharmacol. 2008 Jan 15;75(2):414-26
17945194
Am J Pathol. 2007 May;170(5):1445-53
17456751
J Neuropathol Exp Neurol. 1998 Aug;57(8):791-802
9720494
Autophagy. 2006 Jan-Mar;2(1):58-60
16874033
Cancer Res. 2009 Jun 1;69(11):4769-75
19487289
Drug News Perspect. 2004 Nov;17(9):563-78
15645014
Eur J Pharm Biopharm. 2008 Aug;69(3):817-23
18407478
J Neurochem. 1993 Dec;61(6):2048-53
8245960
Chemotherapy. 2007;53(4):233-56
17595539
Acta Neurochir (Wien). 2009 Feb;151(2):109-12
19194651
Cell Death Differ. 2004 Apr;11(4):448-57
14713959
Neurosurgery. 2008 Jan;62(1):211-21; discussion 221-2
18300910
Cancer Res. 1992 Jul 15;52(14):3972-9
1617673
Clin Cancer Res. 2009 Jul 15;15(14):4622-9
19584161
Cancer Res. 2003 Mar 15;63(6):1207-13
12649178
J Clin Oncol. 2005 Apr 1;23(10):2411-22
15800333
N Engl J Med. 2005 Aug 25;353(8):811-22
16120861
J Cell Physiol. 2005 Mar;202(3):654-62
15389572
Cancer Res. 2002 Mar 15;62(6):1915-9
11912174
Pflugers Arch. 2004 Feb;447(5):480-9
12750891
Glia. 2001 Dec;36(3):375-90
11746774
Cell Death Differ. 2007 Mar;14(3):548-58
16946731
Annu Rev Pathol. 2006;1:97-117
18039109
Neuropsychopharmacology. 2007 Jun;32(6):1251-60
17119541
Cancer Res. 1997 Jul 15;57(14):2933-6
9230204
Oncologist. 2007 Dec;12(12):1395-403
18165616
Hum Pathol. 1993 Aug;24(8):912-20
8375861
J Neurochem. 2006 Nov;99(4):1049-61
16899068
Cancer. 2002 Aug 1;95(3):641-55
12209758
N Engl J Med. 2005 Mar 10;352(10):987-96
15758009
Science. 1956 Feb 24;123(3191):309-14
13298683