A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death.
APR-246
Eprenetapopt
MRP1
glutathione
p53
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
05 02 2021
05 02 2021
Historique:
received:
07
05
2019
revised:
16
11
2020
accepted:
17
11
2020
pubmed:
15
12
2020
medline:
25
11
2021
entrez:
14
12
2020
Statut:
ppublish
Résumé
The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. The compound APR-246 (PRIMA-1Met/Eprenetapopt) is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance. APR-246 is currently tested in a phase III clinical trial in myelodysplastic syndrome (MDS). By in vitro, ex vivo, and in vivo models, we show that combined treatment with APR-246 and inhibitors of efflux pump MRP1/ABCC1 results in synergistic tumor cell death, which is more pronounced in TP53 mutant cells. This is associated with altered cellular thiol status and increased intracellular glutathione-conjugated MQ (GS-MQ). Due to the reversibility of MQ conjugation, GS-MQ forms an intracellular drug reservoir that increases availability of MQ for targeting mutant p53. Our study shows that redox homeostasis is a critical determinant of the response to mutant p53-targeted cancer therapy.
Identifiants
pubmed: 33314700
doi: 10.15252/emmm.201910852
pmc: PMC7863383
doi:
Substances chimiques
Pharmaceutical Preparations
0
Quinuclidines
0
Sulfhydryl Compounds
0
Tumor Suppressor Protein p53
0
eprenetapopt
Z41TGB4080
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e10852Subventions
Organisme : Medical Research Council
ID : RG84369
Pays : United Kingdom
Organisme : Cancer Research UK
ID : RG81771/84119
Pays : United Kingdom
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Nat Med. 2019 May;25(5):850-860
pubmed: 31068703
Antioxidants (Basel). 2017 Aug 03;6(3):
pubmed: 28771170
Cell Death Dis. 2013 Oct 24;4:e881
pubmed: 24157875
EMBO Mol Med. 2021 Feb 5;13(2):e10852
pubmed: 33314700
Free Radic Biol Med. 2009 Dec 1;47(11):1661-71
pubmed: 19766715
Cell Death Differ. 2015 Aug;22(8):1239-49
pubmed: 26024390
Nature. 2019 May;569(7757):503-508
pubmed: 31068700
Cancer Res. 2018 Jun 1;78(11):2925-2938
pubmed: 29510994
Oncogene. 2018 Jun;37(25):3384-3398
pubmed: 29348462
Nat Rev Mol Cell Biol. 2015 Jul;16(7):393-405
pubmed: 26122615
Oncogene. 2005 May 12;24(21):3484-91
pubmed: 15735745
Leuk Res. 2014 Jul;38(7):751-5
pubmed: 24836762
J Neurosci Res. 2002 Aug 1;69(3):318-26
pubmed: 12125073
Nat Med. 2002 Mar;8(3):282-8
pubmed: 11875500
Cell Death Dis. 2015 Jun 18;6:e1794
pubmed: 26086967
Front Pharmacol. 2018 Feb 06;9:31
pubmed: 29467650
Int J Mol Sci. 2018 Jun 26;19(7):
pubmed: 29949936
FEBS Lett. 2006 Feb 13;580(4):1103-11
pubmed: 16387301
Nat Commun. 2013;4:1407
pubmed: 23360998
Mol Ther. 2018 Jun 6;26(6):1482-1493
pubmed: 29735366
BMC Cancer. 2015 Oct 13;15:684
pubmed: 26463477
Bioinformatics. 2017 Aug 01;33(15):2413-2415
pubmed: 28379339
Annu Rev Pharmacol Toxicol. 2014;54:95-117
pubmed: 24050699
Nat Chem Biol. 2016 Feb;12(2):109-16
pubmed: 26656090
Biochem Pharmacol. 2001 Aug 15;62(4):417-24
pubmed: 11448450
Br J Cancer. 2010 Mar 30;102(7):1157-62
pubmed: 20234362
Nat Commun. 2018 Jul 30;9(1):2983
pubmed: 30061675
Biochem J. 2000 Sep 1;350 Pt 2:555-61
pubmed: 10947971
Cancer Biol Ther. 2015;16(5):799-806
pubmed: 25803193
Clin Cancer Res. 2006 Feb 15;12(4):1157-67
pubmed: 16489069
Science. 1998 Nov 20;282(5393):1497-501
pubmed: 9822382
J Biol Chem. 1999 Dec 10;274(50):35809-15
pubmed: 10585464
Cancer Cell. 2019 Feb 11;35(2):177-190.e8
pubmed: 30686770
Blood. 2014 Sep 4;124(10):1626-36
pubmed: 25006124
Br J Haematol. 2016 Jul;174(1):117-26
pubmed: 26991755
J Mol Cell Biol. 2019 Apr 1;11(4):330-341
pubmed: 30892598
Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11400-5
pubmed: 19549867
Cancer Res. 1993 Oct 1;53(19):4469-73
pubmed: 8402615
J Neurochem. 2006 Apr;97(2):373-84
pubmed: 16539673
Cell. 2013 Aug 29;154(5):1151-1161
pubmed: 23993102
Pharmacol Rev. 1989 Jun;41(2):93-141
pubmed: 2692037
Nat Commun. 2017 Mar 28;8:14844
pubmed: 28348409
Comput Struct Biotechnol J. 2015 Sep 25;13:504-13
pubmed: 26949479
Redox Biol. 2014 Apr 18;2:786-94
pubmed: 25009780
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
Transl Oncol. 2018 Dec;11(6):1343-1349
pubmed: 30196236
Clin Cancer Res. 2018 Sep 15;24(18):4505-4517
pubmed: 29914895
Sci Rep. 2016 Jul 18;6:30033
pubmed: 27425006
J Med Chem. 2017 Feb 9;60(3):839-885
pubmed: 27996267
J Exp Clin Cancer Res. 2019 Feb 12;38(1):69
pubmed: 30755224
Biochem Pharmacol. 2000 Jan 1;59(1):25-33
pubmed: 10605931
Biomed Res Int. 2013;2013:143202
pubmed: 24024181
Cancer Cell. 2009 May 5;15(5):376-88
pubmed: 19411067
Arzneimittelforschung. 1953 Jun;3(6):285-90
pubmed: 13081480
Curr Opin Cell Biol. 2018 Apr;51:65-72
pubmed: 29195118
Nature. 2013 Oct 17;502(7471):333-339
pubmed: 24132290
Cell. 2018 Apr 5;173(2):291-304.e6
pubmed: 29625048
Cell Death Dis. 2018 Apr 18;9(5):439
pubmed: 29670092
Nucleic Acids Res. 2020 Jul 2;48(W1):W488-W493
pubmed: 32246720
Anal Biochem. 1969 Mar;27(3):502-22
pubmed: 4388022
Sci Signal. 2013 Apr 02;6(269):pl1
pubmed: 23550210
Cancer Discov. 2015 Nov;5(11):1210-23
pubmed: 26482930
Br J Pharmacol. 2019 Feb;176(4):544-553
pubmed: 30129655
Nat Cell Biol. 2016 Aug;18(8):897-909
pubmed: 27347849
Toxicol Sci. 2016 May;151(1):44-56
pubmed: 26822305
Nat Med. 2005 Dec;11(12):1306-13
pubmed: 16286925
J Biol Chem. 2001 May 11;276(19):15616-24
pubmed: 11278867
J Biomed Res. 2016 Mar;30(2):120-133
pubmed: 28276667
J Clin Oncol. 2012 Oct 10;30(29):3633-9
pubmed: 22965953
J Pathol. 2016 Jan;238(2):321-32
pubmed: 26467985
Sci Rep. 2018 Aug 23;8(1):12671
pubmed: 30140002
Carcinogenesis. 2002 Dec;23(12):2011-8
pubmed: 12507923
Gut. 2015 Oct;64(10):1506-16
pubmed: 26187504
Cancer Cell. 2014 Mar 17;25(3):304-17
pubmed: 24651012
Oncotarget. 2018 Apr 17;9(29):20508-20523
pubmed: 29755668
FEBS Lett. 2000 Mar 3;469(1):47-51
pubmed: 10708754
Cell Rep. 2019 Sep 10;28(11):3010
pubmed: 31509758