NVP-CGM097, an HDM2 Inhibitor, Antagonizes ATP-Binding Cassette Subfamily B Member 1-Mediated Drug Resistance.
ABC transporter
ABCB1
NVP-CGM097
chemotherapy
multidrug resistance
Journal
Frontiers in oncology
ISSN: 2234-943X
Titre abrégé: Front Oncol
Pays: Switzerland
ID NLM: 101568867
Informations de publication
Date de publication:
2020
2020
Historique:
received:
16
04
2020
accepted:
15
06
2020
entrez:
15
8
2020
pubmed:
15
8
2020
medline:
15
8
2020
Statut:
epublish
Résumé
Multidrug resistance (MDR) is a major challenge in the treatment of tumors. It refers to cancer cells become resistant to not only the therapeutic drug, but also cross-resistant to multiple drugs with distinct structures and mechanisms of action when they are exposed to a drug for a period of time. An essential mechanism of MDR is the aberrant expression and function of ATP-binding cassette (ABC) transporters. Therefore, blocking the function of ABC transporters has the therapeutic potential in reversing MDR. The hdm2 oncogene product, HDM2 (also known as MDM2), is an important negative regulator of the p53 tumor suppressor. NVP-CGM097 is an HDM2 inhibitor that can inhibit the proliferation of tumor cells and is currently under clinical trials. In this study, we evaluate whether NVP-CGM097 could reverse ABCB1-mediated MDR. The results of reversal experiment showed that NVP-CGM097 remarkably reversed ABCB1-mediated MDR but not ABCG2-mediated MDR. The results of Western blot and immunofluorescence suggested that the level of expression and subcellular localization of ABCB1 protein were not significantly altered by NVP-CGM097. Mechanism studies indicated that NVP-CGM097 could reverse ABCB1-mediated MDR by directly blocking the ABCB1-mediated drug efflux and raising the accumulation of chemotherapeutic drugs in cancer cells. ATPase analysis showed that low concentration NVP-CGM097 activates ABCB1 ATPase activity while high concentration NVP-CGM097 inhibited ABCB1-associated ATPase. Docking study indicated that NVP-CGM097 tended to bind to the inhibitory site, which led to slight but critical conformational changes in the transporter and reduced the ATPase activity. Overall, our study demonstrates that NVP-CGM097 can be used in conjunction with chemotherapeutic drugs to counteract MDR and improve the antitumor responses.
Identifiants
pubmed: 32793491
doi: 10.3389/fonc.2020.01219
pmc: PMC7390918
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1219Informations de copyright
Copyright © 2020 Zhang, Chen, Dong, Wang, Feng, Teng, Cui, Li, Li and Chen.
Références
Xenobiotica. 2008 Jul;38(7-8):802-32
pubmed: 18668431
Pharmacol Res. 2017 May;119:89-98
pubmed: 28131876
Anticancer Res. 2015 May;35(5):2531-8
pubmed: 25964526
Drug Resist Updat. 2016 Jul;27:14-29
pubmed: 27449595
Chin J Cancer. 2012 Feb;31(2):51-7
pubmed: 22257384
Elife. 2015 May 12;4:
pubmed: 25965177
Front Pharmacol. 2019 Apr 16;10:400
pubmed: 31040786
Neuroendocrinology. 2018;106(1):1-19
pubmed: 27871087
Urol Oncol. 2015 Sep;33(9):385.e15-20
pubmed: 26027763
Br J Cancer. 2014 Aug 12;111(4):716-25
pubmed: 24921920
J Med Chem. 2015 Aug 27;58(16):6348-58
pubmed: 26181851
Cancer Res. 1987 Jun 1;47(11):2961-6
pubmed: 3494506
Front Oncol. 2019 Jun 18;9:514
pubmed: 31275850
Nat Rev Drug Discov. 2006 Mar;5(3):219-34
pubmed: 16518375
Biochim Biophys Acta. 2001 Jun 6;1512(2):171-82
pubmed: 11406094
Front Pharmacol. 2018 Oct 30;9:1236
pubmed: 30425643
J Lipid Res. 2001 Jul;42(7):1007-17
pubmed: 11441126
Curr Cancer Drug Targets. 2013 Mar;13(3):326-46
pubmed: 23369096
Cancers (Basel). 2020 Feb 18;12(2):
pubmed: 32085398
Front Pharmacol. 2018 Oct 09;9:1097
pubmed: 30356705
Crit Rev Biotechnol. 2016 Aug;36(4):716-26
pubmed: 25757878
Biochem Pharmacol. 2020 May;175:113848
pubmed: 32044354
Oncotarget. 2016 Jun 7;7(23):33542-56
pubmed: 27507190
Cancer Control. 2003 Mar-Apr;10(2):159-65
pubmed: 12712010
Int J Cancer. 1991 Nov 11;49(5):696-703
pubmed: 1682280
Biomed Pharmacother. 2019 Dec;120:109468
pubmed: 31605952
J Cancer. 2020 Jan 1;11(1):25-40
pubmed: 31892970
Pharmacol Ther. 2007 Feb;113(2):429-41
pubmed: 17208306
Somat Cell Mol Genet. 1985 Mar;11(2):117-26
pubmed: 3856953
J Comput Chem. 2010 Jan 30;31(2):455-61
pubmed: 19499576
J Biol Chem. 1992 Mar 5;267(7):4854-8
pubmed: 1347044
Eur J Pharmacol. 2019 Nov 15;863:172611
pubmed: 31476282
Cancer Biol Ther. 2015;16(1):106-14
pubmed: 25482933
Drug Resist Updat. 2018 Nov;41:1-25
pubmed: 30471641
Biochem Biophys Res Commun. 2016 Aug 5;476(4):183-187
pubmed: 27286705
Mol Cancer Ther. 2013 Sep;12(9):1829-36
pubmed: 23861346
J Agric Food Chem. 2020 Mar 25;68(12):3850-3858
pubmed: 32167760
Science. 2019 Feb 15;363(6428):753-756
pubmed: 30765569
Cancer Lett. 2018 May 1;421:186-198
pubmed: 29331420
Cancer Res. 2014 Jan 15;74(2):598-608
pubmed: 24305879
Mol Med Rep. 2014 Apr;9(4):1439-43
pubmed: 24549588
Cancer Lett. 2019 Jan;440-441:82-93
pubmed: 30315846
Pharmazie. 2014 Jan;69(1):48-54
pubmed: 24601223
Crit Rev Ther Drug Carrier Syst. 2015;32(3):247-75
pubmed: 26080810
Mol Pharm. 2012 Jul 2;9(7):1971-82
pubmed: 22632055
Nature. 1992 Jul 2;358(6381):80-3
pubmed: 1614537