Histone deacetylase inhibition enhances the therapeutic effects of methotrexate on primary central nervous system lymphoma.
histone deacetylase inhibitor
leucovorin
methotrexate
polyglutamylation
primary central nervous system lymphoma
Journal
Neuro-oncology advances
ISSN: 2632-2498
Titre abrégé: Neurooncol Adv
Pays: England
ID NLM: 101755003
Informations de publication
Date de publication:
Historique:
entrez:
15
8
2020
pubmed:
15
8
2020
medline:
15
8
2020
Statut:
epublish
Résumé
Polyglutamylation is a reversible protein modification that commonly occurs in tumor cells. Methotrexate (MTX) in tumor cells is polyglutamylated and strongly binds to dihydrofolate reductase (DHFR) without competitive inhibition by leucovorin. Therefore, tumor cells with high polyglutamylation levels are supposed to be selectively killed, whereas normal cells with lower polyglutamylation are rescued by leucovorin. This study investigated the combined effects of MTX plus histone deacetylase inhibitors (HDACIs), which upregulate MTX polyglutamylation, in primary central nervous system lymphoma (PCNSL). We evaluated cell viability after MTX treatment and leucovorin rescue and compared the expression of folylpolyglutamate synthetase (FPGS), γ-glutamyl hydrolase (GGH), and DHFR in 2 human PCNSL-derived cell lines (HKBML and TK) and a human Burkitt lymphoma cell line (TL-1). Combination treatments were created using 4 HDACIs: panobinostat, vorinostat, sodium butyrate, and valproic acid. The expression of DHFR was examined as well as ratios of FPGS/GGH expression. The combined effects of MTX plus HDACIs were evaluated using a cell viability assay, mass spectroscopy imaging, and subcutaneous and intracranial xenograft models. HDACIs upregulated the ratio of FPGS/GGH expression resulting in increased polyglutamylation of MTX, but also downregulated expression of the target molecule of MTX: DHFR. The combination of MTX and vorinostat decreased cell viability in vitro ( HDACIs enhanced the therapeutic effect of MTX through increased polyglutamylation of MTX and concomitant downregulation of DHFR expression.
Sections du résumé
BACKGROUND
BACKGROUND
Polyglutamylation is a reversible protein modification that commonly occurs in tumor cells. Methotrexate (MTX) in tumor cells is polyglutamylated and strongly binds to dihydrofolate reductase (DHFR) without competitive inhibition by leucovorin. Therefore, tumor cells with high polyglutamylation levels are supposed to be selectively killed, whereas normal cells with lower polyglutamylation are rescued by leucovorin. This study investigated the combined effects of MTX plus histone deacetylase inhibitors (HDACIs), which upregulate MTX polyglutamylation, in primary central nervous system lymphoma (PCNSL).
METHODS
METHODS
We evaluated cell viability after MTX treatment and leucovorin rescue and compared the expression of folylpolyglutamate synthetase (FPGS), γ-glutamyl hydrolase (GGH), and DHFR in 2 human PCNSL-derived cell lines (HKBML and TK) and a human Burkitt lymphoma cell line (TL-1). Combination treatments were created using 4 HDACIs: panobinostat, vorinostat, sodium butyrate, and valproic acid. The expression of DHFR was examined as well as ratios of FPGS/GGH expression. The combined effects of MTX plus HDACIs were evaluated using a cell viability assay, mass spectroscopy imaging, and subcutaneous and intracranial xenograft models.
RESULTS
RESULTS
HDACIs upregulated the ratio of FPGS/GGH expression resulting in increased polyglutamylation of MTX, but also downregulated expression of the target molecule of MTX: DHFR. The combination of MTX and vorinostat decreased cell viability in vitro (
CONCLUSION
CONCLUSIONS
HDACIs enhanced the therapeutic effect of MTX through increased polyglutamylation of MTX and concomitant downregulation of DHFR expression.
Identifiants
pubmed: 32793886
doi: 10.1093/noajnl/vdaa084
pii: vdaa084
pmc: PMC7415262
doi:
Types de publication
Journal Article
Langues
eng
Pagination
vdaa084Informations de copyright
© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
Références
Nat Rev Neurol. 2013 Jun;9(6):317-27
pubmed: 23670107
Acta Neuropathol. 2016 Jun;131(6):865-75
pubmed: 26757737
Nat Rev Drug Discov. 2006 Sep;5(9):769-84
pubmed: 16955068
Biochim Biophys Acta. 2002 Jul 18;1587(2-3):164-73
pubmed: 12084458
Nat Rev Cancer. 2001 Dec;1(3):194-202
pubmed: 11902574
J Biol Chem. 1985 Aug 15;260(17):9720-6
pubmed: 2410416
Semin Oncol. 1997 Oct;24(5 Suppl 18):S18-30-S18-39
pubmed: 9420019
Mol Cancer Ther. 2003 Feb;2(2):151-63
pubmed: 12589032
Clin Cancer Res. 2007 Feb 1;13(3):1045-52
pubmed: 17289901
Oncogene. 2007 Aug 13;26(37):5541-52
pubmed: 17694093
J Neurosurg. 1999 Aug;91(2):221-30
pubmed: 10433310
Cancer Res. 2000 Sep 15;60(18):5165-70
pubmed: 11016644
Semin Oncol. 1999 Apr;26(2 Suppl 6):24-32
pubmed: 10598551
Cancer Res. 1985 Dec;45(12 Pt 1):6395-400
pubmed: 2415244
Acta Neuropathol Commun. 2018 Feb 23;6(1):15
pubmed: 29475458
Cancer Res. 2013 Apr 1;73(7):2333-44
pubmed: 23365134
J Neurosurg. 1989 Feb;70(2):190-4
pubmed: 2913217
Acta Neuropathol. 2017 Feb;133(2):321-324
pubmed: 28058506
Cancer Chemother Pharmacol. 2014 Nov;74(5):1029-32
pubmed: 25205429
J Neurochem. 2005 May;93(4):992-9
pubmed: 15857402
J Clin Oncol. 2005 Aug 1;23(22):5034-43
pubmed: 15955902
Cancer Res. 1984 Aug;44(8):3190-5
pubmed: 6204743
Oncologist. 1996;1(4):223-226
pubmed: 10387992
J Basic Clin Pharm. 2016 Mar;7(2):27-31
pubmed: 27057123
Cancer Res. 2003 Nov 1;63(21):7291-300
pubmed: 14612526
Leukemia. 2010 Mar;24(3):552-62
pubmed: 20072153
Annu Rev Nutr. 2001;21:255-82
pubmed: 11375437
Cell Rep. 2019 Oct 1;29(1):89-103.e7
pubmed: 31577958
Mol Cancer Res. 2007 Oct;5(10):981-9
pubmed: 17951399
Eur J Cancer Clin Oncol. 1987 Jun;23(6):843-7
pubmed: 3477462
Mol Pharmacol. 1997 Jul;52(1):155-63
pubmed: 9224825
J Clin Oncol. 2009 Apr 20;27(12):2052-8
pubmed: 19307505
Gut. 2004 Dec;53(12):1825-31
pubmed: 15542523
N Engl J Med. 1996 Oct 3;335(14):1041-8
pubmed: 8793930
J Neurooncol. 2007 Jul;83(3):267-75
pubmed: 17310267
Cancer Res. 1988 Apr 15;48(8):2149-55
pubmed: 2450647
Curr Pharm Des. 2003;9(31):2593-613
pubmed: 14529544
Cancer Res. 1986 Feb;46(2):588-93
pubmed: 2416428